Glucocorticoid-Mediated Modulation of Eosinopoiesis in Asthma: A Paradoxical Duality

Abstract

Glucocorticoids (GCs) remain the cornerstone of asthma treatment due to their potent anti-inflammatory and eosinophil-suppressive effects in the airways, including the induction of peripheral eosinophil apoptosis and downregulation of type 2 cytokine signaling. However, emerging evidence reveals a paradoxical role for GCs in the bone marrow, where they enhance eosinophil production (eosinopoiesis), especially under allergic, infectious, or surgical stress conditions. This duality reflects a complex immunoendocrine interplay involving GC-induced modulation of eosinophil progenitor survival, proliferation, and responsiveness to eosinopoietic cytokines such as interleukin-5 and granulocyte-macrophage colony-stimulating factor. Furthermore, GCs synergize with lipid mediators like cysteinyl-leukotrienes and prostaglandins, modulating both transcriptional and adhesion molecule profiles that prime eosinophil precursors for migration and differentiation. This review examines the molecular and cellular mechanisms underlying GC-induced eosinopoiesis, its functional link to airway inflammation, and its clinical implications for asthma management. We also explore potential therapeutic strategies aimed at selectively modulating bone marrow eosinophil output without compromising the peripheral anti-inflammatory benefits of GCs. Understanding this paradoxical duality holds significant translational potential for improving disease control and preventing asthma exacerbations.

1. Introduction

Glucocorticoids (GCs) remain the cornerstone of asthma management due to their well-established anti-inflammatory and immunosuppressive properties. By binding to the glucocorticoid receptor (GCR), GCs exert transcriptional and post-transcriptional control over a wide array of inflammatory mediators, leading to decreased production of key Th2 cytokines (interleukin(IL)-4, IL-5, IL-13) [1,2,3,4]. In the context of asthma—a chronic, heterogeneous inflammatory disease characterized by airway hyperresponsiveness, mucus overproduction, and airway eosinophilia. GCs suppress type 2 helper T cell-driven responses, reduce cytokine production, and promote apoptosis of infiltrating eosinophils, decreasing airway eosinophilia [3,4]. Their efficacy in mitigating airway inflammation and restoring pulmonary function underlies their use in both acute exacerbations and long-term management. Clinically, this translates into improved lung function, reduced exacerbation frequency, and enhanced asthma control, especially when inhaled corticosteroids are administered chronically [3,4]. Systemic corticosteroids are typically reserved for severe asthma cases or acute exacerbations.

However, recent murine studies have highlighted a complex, context-dependent role of GCs that extends beyond their classical anti-inflammatory effects. Specifically, their paradoxical action in enhancing eosinophil production (eosinopoiesis) within the bone marrow has gained attention. Early work demonstrated that allergen challenges, surgical stress, and even bacterial antigen exposures can trigger GC-dependent increases in eosinophil progenitors and mature eosinophils in the bone marrow compartment [5,6,7,8]. This effect contrasts sharply with their peripheral suppressive action and points to a systemic immunoendocrine regulation that connects stress responses, hematopoiesis, and allergic inflammation [7,9].

The phenomenon has been observed across diverse experimental models, including intranasal challenge after sensitization, surgical implantation of antigens, and exposure to Staphylococcal enterotoxins [6,8]. Moreover, GCs can synergize with eosinopoietic cytokines (e.g., IL-5), lipid mediators (e.g., cysteinyl-leukotrienes (CysLT)), and even with bone marrow stromal cell-derived factors to promote eosinophil lineage commitment and survival [10,11,12,13]. Notably, this central action of GCs is often masked clinically due to their concurrent peripheral eosinophil-suppressive effects, but it holds profound implications for asthma relapse, corticosteroid resistance, and systemic eosinophilic syndromes.

This review will explore the mechanistic underpinnings of GC-mediated eosinopoiesis in asthma, focusing on cytokine interactions, bone marrow microenvironmental changes, and the broader immunological context that frames this paradoxical duality. We will also address the clinical implications and propose future directions for research and therapy development.

2. General Aspects of Eosinopoiesis: Cellular Pathways and Transcriptional Control

Eosinopoiesis refers to the highly regulated process by which multipotent hematopoietic stem cells differentiate into mature eosinophils. This process primarily occurs in the bone marrow and is governed by a complex interplay of cytokines, transcription factors, and bone marrow microenvironmental cues [14,15].

At the cellular level, eosinophil development proceeds from common myeloid progenitors to granulocyte-monocyte progenitors and finally to eosinophil lineage-committed progenitors. Eosinophil progenitors are characterized by co-expression of CD34 and IL-5 receptor alpha (IL-5Rα) [14]. IL-5 is the most specific and critical cytokine for driving terminal eosinophil differentiation and survival [16].

Transcriptional regulation of eosinophil commitment involves the coordinated action of key transcription factors, notably GATA-1, GATA-2, C/EBPα, and IRF8 [14,17]. Recent studies in zebrafish and mammalian models have highlighted the role of the Cebp1/Cebpβ axis in balancing eosinophil versus neutrophil lineage commitment, emphasizing the evolutionary conservation of this regulatory network [17]. Furthermore, IL5RA gene expression itself is dynamically regulated during eosinophil maturation through the use of alternative promoters (P1 and P2) and the differential binding of transcription factors like GATA-1 and PU.1 [15].

The earliest committed precursor, the myeloblast, is characterized by robust proliferative potential and expression of general myeloid transcription factors. Progression to the promyelocyte stage is marked by the initiation of primary granule protein synthesis and the emergence of early eosinophil lineage markers. In the myelocyte stage, secondary granule biogenesis commences, accompanied by increased expression of eosinophil-specific granule proteins such as major basic protein (MBP) and eosinophil peroxidase (EPX). The final metamyelocyte stage represents terminal differentiation, with complete granule maturation and the acquisition of functional surface markers [18,19,20,21,22].

At the transcriptional level, the myeloblast-to-promyelocyte transition is driven by activation of PU.1 (Spi1), which binds to eosinophil-specific enhancers, thereby initiating lineage commitment and early granule gene transcription [23,24]. This stage is also characterized by upregulation of the long non-coding RNA EGO, essential for the optimal expression of MBP and eosinophil-derived neurotoxin (EDN), and by the repression of genes associated with alternative myeloid fates, such as neutrophil-specific programs [25,26]. The promyelocyte-to-myelocyte transition involves the increased activity of C/EBPε and GATA-1, with C/EBPε being indispensable for secondary granule gene expression and GATA-1 directly transactivating MBP [24,25,27]. During this stage, GATA-2 acts as a negative regulator by repressing MBP and possibly other eosinophil-specific genes [27]. The myelocyte-to-metamyelocyte transition and subsequent maturation involve the upregulation of Ikaros family members, such as Helios and Aiolos, which regulate chromatin accessibility and control the expression of genes involved in migration (e.g., CCR3), degranulation, and survival [23,26,28]. In parallel, eosinophil-specific superenhancers enriched for allergic disease–associated risk loci become active. Downregulation of Id1 and upregulation of Id2 facilitate terminal maturation [29].

Additional regulatory elements play critical roles throughout granulopoiesis. XBP1 is selectively required for proper granule protein maturation and secretory pathway homeostasis [30]. PU.1 and C/EBPε function cooperatively to activate eosinophil granule genes, and the loss of either factor impairs MBP and EPX expression [24]. Epigenetic mechanisms, particularly H3K27 acetylation at active enhancers, are central to establishing and maintaining eosinophil lineage identity, with superenhancers orchestrating the expression of genes crucial for eosinophil effector functions [23,26].

From an immunophenotypic perspective, recent flow cytometry studies [31] have provided detailed characterization of human bone marrow eosinophil differentiation stages. Markers such as Siglec-8, CD11b, CD49d, and CD125 (IL-5Rα) display stage-specific expression patterns, enabling refined identification of eosinophil maturation states under both physiological and pathological conditions.

For a comprehensive visual representation of eosinophil granulopoiesis, including the sequential stages from hematopoietic stem cell to mature eosinophil, the associated transcription factors, and stage-specific markers, see detailed figures in [32,33].

Importantly, eosinopoiesis can be modulated by both endogenous factors and pharmacological agents. For example, dexamethasone has been shown to suppress eosinophil granule protein production and induce apoptosis in IL-5-driven cultures of umbilical cord blood progenitors [34]. Furthermore, environmental stressors, such as systemic infection or inflammation (as modeled by human endotoxemia), can alter bone marrow eosinophil dynamics without significantly affecting progenitor pool size, suggesting that mobilization, rather than production, is acutely regulated in such contexts [35].

Lastly, novel insights into the non-traditional roles of eosinophils—including their participation in adipose tissue homeostasis, immune metabolism, and tissue remodeling—are expanding the clinical relevance of understanding eosinopoiesis beyond allergic diseases [36].

3. Classical Role of Glucocorticoids on Asthma

GCs represent the cornerstone of anti-inflammatory therapy for asthma, particularly for eosinophilic phenotypes of the disease. Their classical mechanisms involve both genomic and non-genomic actions that regulate eosinophil survival and promote apoptosis, contributing to the resolution of airway inflammation [37].

GCs mediate eosinophil apoptosis primarily via activation of the GCR, a nuclear receptor that modulates gene transcription. Upon ligand binding, GCR translocates to the nucleus, where it can either upregulate anti-inflammatory genes (transactivation) or suppress pro-inflammatory genes (transrepression) [37]. Specifically, GCs downregulate survival signals driven by cytokines like IL-5, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-3, and can directly initiate the intrinsic mitochondrial apoptotic pathway in eosinophils [38].

At the molecular level, glucocorticoids increase mitochondrial membrane permeabilization, leading to the release of cytochrome c, activation of caspase-9, and subsequent activation of downstream executioner caspases, resulting in DNA fragmentation and cellular apoptosis [38]. Additionally, GCs can influence Fas-mediated extrinsic apoptotic pathways, further enhancing eosinophil clearance from the airways [39].

In asthmatic patients, GC therapy actively increases eosinophil apoptosis, reducing the survival of these cells within inflamed airways. For example, Kankaanranta et al. [40] observed that peripheral blood eosinophils from steroid-naïve asthmatic patients exhibit delayed apoptosis, a phenomenon reversed upon corticosteroid treatment. Similarly, Bates et al. [41] reported that airway eosinophils, after allergen challenge, display upregulated anti-apoptotic gene profiles, suggesting that GCs are required to counteract this survival programming.

Importantly, in vitro studies confirm that GCs like mometasone, budesonide, and fluticasone can accelerate eosinophil apoptosis in a concentration-dependent manner, even in the presence of survival-promoting cytokines [41,42]. Interestingly, GCs show cell-type specificity, inducing apoptosis in eosinophils, but often delaying apoptosis in neutrophils, a divergence likely related to differences in intracellular signaling pathways [37].

Efficient resolution of inflammation requires not only eosinophil apoptosis but also their non-inflammatory removal by phagocytes, particularly macrophages and airway epithelial cells [37,38]. GCs enhance this clearance process by upregulating phagocytic receptors and bridging molecules like Annexin-1, promoting rapid engulfment of apoptotic eosinophils and preventing secondary necrosis [37].

The ability of GCs to induce eosinophil apoptosis underpins their therapeutic efficacy in controlling eosinophilic inflammation in asthma. This is particularly evident in patients with severe eosinophilic asthma, where failure to induce eosinophil apoptosis is associated with steroid resistance and persistent airway eosinophilia [38].

Beyond GCs, other asthma medications, such as theophylline, macrolides, and β2-agonists, have been shown to modulate eosinophil survival, although often through distinct and less potent pathways [39,42]. Although those medications are not part of the standard therapy for asthma, but may be considered in selected cases, such as patients with specific phenotypes or comorbidities, or when conventional treatments fail to achieve adequate control. Understanding these pathways offers potential for combination therapies aimed at enhancing eosinophil apoptosis and clearance. A summary of the canonical effects of GCs is shown in Figure 1.

4. GC-Induced Eosinopoiesis

While GCs exert well-characterized pro-apoptotic effects on mature eosinophils in peripheral tissues, leading to the resolution of airway inflammation, their impact on the bone marrow compartment reveals a striking immunoendocrine paradox. Instead of promoting cell death at the progenitor level, in murine models, GCs can enhance eosinophil production in the context of allergen exposure. The GCs act within the bone marrow microenvironment to enhance eosinopoiesis, increasing both the number and responsiveness of eosinophil precursors. This dichotomy highlights the compartment-specific and maturation stage-dependent actions of GCs, where the same hormonal signal that induces apoptosis in peripheral, fully differentiated eosinophils simultaneously fosters the survival, proliferation, and differentiation of their progenitors within the marrow. Understanding this dualism is essential for unraveling the systemic dynamics of eosinophil homeostasis in asthma and for designing therapies that can selectively target eosinophilic inflammation without exacerbating hematopoietic eosinophil output.

Although the capacity of glucocorticoids to enhance eosinophil production in the bone marrow during allergen exposure has been predominantly demonstrated in murine models, some data in humans provide a more nuanced perspective. In vitro assays using unpurified human bone marrow cells indicate that GCs often inhibit eosinophil colony formation indirectly, via suppression of IL-5 and GM-CSF production by accessory cells. However, when purified CD34⁺ progenitors are stimulated directly with recombinant cytokines, glucocorticoids do not impair eosinophil colony formation [43]. In a study by Butterfield et al. [44], administration of prednisolone to healthy donors resulted in increased bone marrow eosinophilia, indicating that this paradoxical effect is not restricted to experimental animal models. These findings highlight the complexity of GC effects on human eosinopoiesis, which may vary depending on cytokine availability and cellular context.

The capacity of GCs to enhance eosinophil production in the bone marrow represents a complex and highly regulated biological process. Unlike their suppressive role on peripheral eosinophilic inflammation, GCs act within the bone marrow microenvironment to prime progenitor cells for enhanced eosinopoietic responsiveness, particularly under conditions of allergen exposure, stress, or infection [6,10]. In the allergen exposure model, this response is dependent on tumor necrosis factor alpha (TNF-α) and its receptor TNFR1, which together with GCs constitute an immunoendocrine axis essential for allergen-induced eosinopoiesis [7].

An important but often overlooked feature of GC-induced eosinopoiesis is its priming by systemic stressors, including trauma, surgical procedures, and infections. Experimental models demonstrate that surgical stress alone, even in the absence of allergen exposure, is sufficient to trigger a marked GC-dependent increase in bone marrow eosinophil progenitors and mature eosinophils [6,9].

This hematopoietic “preconditioning” effect appears to be an adaptive immunoendocrine response, allowing the organism to prepare for potential secondary immune challenges following tissue injury [45]. The underlying mechanisms involve a surge in endogenous GCs, which act synergistically with low-level basal cytokine signals to expand the eosinophil compartment.

Similarly, infections—particularly those involving microbial products that engage Toll-like receptors (TLRs)—may amplify GC-driven eosinopoiesis, though the specific pathways remain underexplored [45]. While certain parasitic and viral infections can lead to transient eosinophilia, the majority of infections in humans are accompanied by eosinopenia, a phenomenon generally attributed to stress-induced glucocorticoid release and redistribution of eosinophils to tissues [46,47].

One pivotal mechanism underlying this effect is the synergistic interaction between GCs and eosinopoietic cytokines, especially IL-5 and GM-CSF. Dexamethasone has been shown to upregulate the responsiveness of eosinophil progenitors to both IL-5 and GM-CSF, enhancing colony formation and promoting terminal differentiation [5,10]. This synergy is partly explained by GC-induced upregulation of cytokine receptors on hematopoietic progenitors, thereby sensitizing these cells to even low levels of eosinopoietic stimuli [10,48].

Moreover, GCs modulate apoptotic pathways in eosinophil precursors. Experimental models suggest that dexamethasone inhibits apoptosis in maturing eosinophils, potentially by altering expression of anti-apoptotic proteins or through interference with nitric oxide (NO)-dependent signaling cascades [11,49]. This anti-apoptotic effect may prolong the survival of eosinophil precursors, further amplifying the eosinophilic response.

GCs also exert non-linear effects on hematopoietic progenitor maturation stages, selectively influencing eosinophil lineage commitment while sparing or even suppressing other myeloid lineages [11]. This stage-specificity suggests that GCs engage with transcriptional programs unique to eosinophil progenitors, potentially involving GATA family transcription factors or other lineage-defining regulators. However, the precise molecular determinants remain incompletely understood.

Another important modulator of GC-driven eosinopoiesis is the CysLT pathway. GCs synergize with CysLTs—lipid mediators derived from the 5-lipoxygenase pathway—to enhance eosinophil output from bone marrow. This cooperation has been demonstrated both in vitro and in vivo, with pharmacological blockade of CysLT1 receptors (e.g., montelukast) abolishing GC-induced eosinopoiesis in allergen-challenged mice [11,50].

Furthermore, inflammatory cytokines with anti-eosinopoietic properties, such as IL-17A, or inflammatory mediators, such as prostaglandin E2, are actively counter-regulated by GCs. IL-17A suppresses eosinopoiesis by inducing NO-mediated, CD95-dependent apoptosis in eosinophil progenitors—a process that GCs effectively block by downregulating inducible NO synthase (iNOS) expression [51]. Similarly, GCs antagonize prostaglandin E2-induced suppression of eosinopoiesis by interfering with NO and CD95L pathways [52].

Interestingly, retinoic acid also acts as a negative regulator of eosinopoiesis, primarily through iNOS-dependent apoptosis of eosinophil progenitors. This suppression is reversible by GCs or by genetic disruption of iNOS, further emphasizing the capacity of GCs to protect eosinophil progenitors from diverse pro-apoptotic stimuli [11].

Lastly, cytotoxic lymphocyte pathways, particularly those mediated by perforin, are essential for GC-induced eosinopoiesis. In perforin-deficient mice, the eosinopoietic response to dexamethasone is abolished, but can be restored by the adoptive transfer of lymphocytes from wild-type donors [53]. This observation highlights the interplay between adaptive immune cells and hematopoietic niches in modulating GC effects.

A pivotal cellular component in GC-mediated eosinopoiesis is the population of CD34+/IL-5Rα+ progenitor cells, which represent committed precursors in the eosinophil lineage. These progenitors display remarkable functional plasticity, capable of rapidly altering their proliferative and migratory responses in accordance with systemic immunological cues.

Experimental models of allergen sensitization have shown that both the frequency and activation status of CD34+/IL-5Rα+ progenitors significantly increase within the bone marrow following airway inflammatory challenges [8]. Importantly, these progenitors not only respond to classical eosinopoietic cytokines like IL-5 and GM-CSF but also exhibit altered expression of surface molecules critical for trafficking, such as CCR3 and VLA-4, further linking their differentiation status to mobilization capacity.

Moreover, the combination of GCs with type 2 cytokines and lipid mediators appears to synergistically enhance the differentiation and survival of these progenitors, expanding the pool of eosinophils available for peripheral tissue recruitment. These observations suggest that CD34+/IL-5Rα+ progenitors act as an immunological amplifier, integrating GC signaling with environmental and allergen-derived inputs to shape the systemic eosinophilic response in asthma.

At the intracellular level, signal transducer and activator of transcription 5 (STAT5) has emerged as a key regulator of GC-induced eosinopoiesis. Studies using human CD34+ hematopoietic progenitor cells have demonstrated that exposure to dexamethasone leads to a significant increase in STAT5 phosphorylation, especially when combined with IL-5 stimulation [54].

STAT5 activation appears to promote both proliferation and terminal differentiation of eosinophil precursors, suggesting that GCs potentiate IL-5 signaling through this intracellular pathway [54]. Interestingly, different STAT5 isoforms are engaged at distinct stages of eosinophil development, reflecting a phase-specific regulatory mechanism.

The pharmacological inhibition of STAT5 signaling partially abrogates the GC-enhanced eosinopoietic response, further confirming its functional relevance [55,56]. These findings position STAT5 as a potential molecular target for future therapeutic strategies aiming to uncouple the anti-inflammatory benefits of GCs from their eosinopoietic side effects. Notably, STAT5 inhibitors are currently under investigation for the treatment of some leukemias [57,58].

GCs have been shown to modulate autophagy pathways in hematopoietic cells, an effect that may influence eosinophil differentiation and survival. In certain contexts, GC signaling can enhance autophagic flux, potentially altering the balance between cell survival and apoptosis [59]. This dual regulation suggests that autophagy may act as a modulatory checkpoint in GC-driven eosinopoiesis, representing another potential target to modulate bone marrow eosinophil output without compromising peripheral anti-inflammatory actions.

Recent advances in immunometabolism and cell biology have uncovered a critical role for autophagy-related protein 5 (ATG5) in eosinophil differentiation and survival. In murine models with hematopoietic-specific ATG5 deletion, eosinophil lineage commitment and maturation are profoundly impaired, resulting in reduced eosinophil counts both in the bone marrow and peripheral tissues [60,61].

ATG5-mediated autophagy appears to be essential for maintaining cellular homeostasis during high metabolic demand states, such as those induced by GCs [61]. Although direct interactions between GCs and the autophagy machinery in eosinophil progenitors remain to be fully elucidated, existing data suggest that GC-driven eosinopoiesis may, at least partially, depend on intact autophagic processes to support progenitor survival and differentiation under stress conditions.

Together, these findings establish that GC-driven eosinopoiesis is a multifactorial, stage-selective, and cytokine-modulated process, deeply embedded in the immunological and microenvironmental context of the bone marrow.

5. The Bone Marrow Microenvironment and External Modulators of GC-Induced Eosinopoiesis

The bone marrow microenvironment plays a critical role in determining the magnitude and quality of eosinophil production under GC influence. Far from acting on hematopoietic progenitors in isolation, GCs exert their effects within a complex cellular and molecular niche [11,12]. The non-hematopoietic components provide essential signals—both soluble and contact-dependent—that synergize with GCs to regulate eosinophil lineage commitment, proliferation, and survival.

Bone marrow stromal cells, including fibroblasts and osteoblast-lineage cells, produce cytokines, adhesion molecules (e.g., VCAM-1), and extracellular matrix proteins that condition the hematopoietic niche [12]. The interaction between eosinophil progenitors and VCAM-1 via VLA-4 integrins is modulated during GC-driven eosinopoiesis, influencing both retention within the marrow and readiness for mobilization [8].

Bacterial antigens, such as Staphylococcal enterotoxins A and B (SEA, SEB), represent another layer of extrinsic regulation. Airway exposure to SEA has been shown to potentiate allergen-induced bone marrow eosinophilia and accelerate eosinophil trafficking from marrow to blood and lungs [8]. This effect involves upregulation of IL-5 and eotaxin within the bone marrow and modulation of eosinophil adhesion molecule expression, favoring mobilization. Given that staphylococcal antigens also reduce T-cell sensitivity to steroids [8], their impact on GC-driven eosinopoiesis raises intriguing possibilities for steroid-resistant asthma phenotypes.

In murine models, this exposure to bacterial antigens also significantly reduces the expression of CCR3 and VLA-4 integrins on bone marrow eosinophils, both of which are essential for eosinophil retention within the marrow microenvironment via interactions with VCAM-1 [8].

This downregulation of adhesion molecules facilitates the detachment and mobilization of eosinophils, promoting their entry into circulation and subsequent recruitment to inflamed airway tissues. Importantly, this process is potentiated by GCs, which may act in concert with SEA-induced signals to reprogram eosinophil surface receptor profiles. Surgical stress and trauma similarly provoke GC-dependent eosinophil production. In murine models, surgical injury leads to systemic GC elevation and robust eosinophilic responses in the bone marrow, even in the absence of allergen exposure [5,9]. This response is completely abrogated by adrenalectomy, metyrapone, or the GC receptor antagonist RU486, reinforcing the centrality of endogenous GCs in stress-induced eosinopoiesis [5].

In response to systemic infections, trauma, or severe allergic inflammation, the bone marrow can initiate “emergency eosinopoiesis”, characterized by rapid expansion of eosinophil progenitors and accelerated maturation kinetics [36].

In human models of experimental endotoxemia, this process occurs without significant expansion of progenitor pools, suggesting that mobilization and accelerated maturation, rather than de novo progenitor proliferation, drive the acute eosinophilic response [35]. In asthma, this mechanism may contribute to acute exacerbations, particularly in the setting of concurrent viral or bacterial infections.

Importantly, GCs can act as both triggers and amplifiers of emergency eosinopoiesis, depending on the inflammatory context and co-existing cytokine environment. Neuroimmune interactions further contribute to this regulation. Sensory nerve activation and neuropeptide release (e.g., substance P) have been implicated in modulating marrow output in other granulocyte lineages, although their role in eosinopoiesis remains to be fully characterized [8,62]. Chronic infections, environmental pollutants, and metabolic factors like hypoxia and oxidative stress can reshape the marrow niche, potentially altering the balance between GC-induced eosinophil expansion and suppression [8,12].

Besides eosinophil production, the eosinophil mobilization from the bone marrow to peripheral circulation and inflamed tissues represents a crucial downstream step following GC-induced eosinopoiesis. This process is tightly regulated by chemokines such as eotaxin and cytokines like IL-5, which together orchestrate progenitor egress, bloodstream survival, and tissue recruitment. Experimental exposure to SEA in mice has been shown to accelerate allergen-induced eosinophil mobilization by modulating the expression of CCR3 and VLA-4 integrins on bone marrow eosinophils. These adhesion and chemokine receptors mediate eosinophil binding to VCAM-1 within the marrow stroma, and their downregulation after SEA exposure enhances eosinophil release into circulation [8].

Interestingly, this mobilization is not merely passive; it represents an active modulation of eosinophil migratory readiness induced by combined signals from microbial products, GCs, and local stromal interactions. These findings emphasize that GC-driven eosinopoiesis in asthma is coupled not only to increased production but also to enhanced tissue recruitment potential, particularly in settings of microbial colonization or airway superantigen exposure.

Collectively, these findings highlight that GC-induced eosinopoiesis does not occur in a vacuum. It is orchestrated within a dynamic bone marrow microenvironment, influenced by local stromal signals and systemic immune-endocrine cues, as well as by external environmental and microbial factors. Most of the observations regarding the role of the bone marrow microenvironment and external modulators in GC-induced eosinopoiesis originate from murine models. Although these studies have provided valuable mechanistic insights, translation to human physiology remains limited, with only a few reports addressing these aspects in clinical or ex vivo human settings. Understanding this network of interactions is essential for translating basic research findings into clinically relevant strategies for asthma management.

A summary of the paradoxical effects of GCs is shown in Figure 2.

6. Bone Marrow Priming and Cellular Mechanisms of GC-Dependent Eosinopoiesis in Experimental Asthma

The study by Vieira et al. [62] provides critical mechanistic insights into how GCs, in concert with lipid mediators, orchestrate not only eosinophil production but also the functional priming of the bone marrow compartment during allergic airway inflammation in mice.

In the ovalbumin sensitization and challenge model, the airway allergen exposure triggers a systemic hematopoietic response characterized by increased frequencies of eosinophil progenitors and mature eosinophils in the bone marrow, a phenomenon strictly dependent on endogenous GC signaling. This “bone marrow priming” is functionally evident by a heightened eosinopoietic responsiveness of bone marrow cells to ex vivo stimulation with eosinopoietic cytokines.

Importantly, the distinct changes in adhesion molecule expression on bone marrow eosinophils and progenitors involve VLA-4-mediated trafficking. After allergen challenge, there was a significant upregulation of VLA-4 expression, enhancing eosinophil migration potential and responsiveness within the bone marrow microenvironment. This suggests that GCs, together with inflammatory signals, induce a molecular phenotype in bone marrow eosinophils that favors both their expansion and readiness for peripheral recruitment.

Further mechanistic dissection reveals that both 5-lipoxygenase activity and CysLT1 receptor signaling are essential cofactors in the priming process. Pharmacological blockade of these pathways prevented the allergen-induced increases in eosinophil counts and abolished the upregulation of adhesion molecules, even in the presence of intact GC signaling. This indicates that GCs require concurrent leukotriene-mediated signals to fully execute their eosinopoietic and priming functions.

Additionally, the study observed that the peripheral eosinophilic response in the lungs mirrored the changes observed in the bone marrow, establishing a clear functional link between marrow priming and airway eosinophilia.

Beyond cytokine and immune signaling, transcriptional control plays a pivotal role in eosinophil lineage commitment. Central transcription factors include GATA-1, C/EBPα, PU.1, and IRF8, which coordinate the expression of eosinophil-specific genes [14,17].

Recent studies highlight that the IL5RA gene, which encodes the IL-5 receptor alpha chain, undergoes alternative promoter usage (P1 and P2), with differential regulation during various eosinophil maturation stages [15]. Furthermore, epigenetic modifications such as histone acetylation, DNA methylation, and microRNA-mediated post-transcriptional control modulate eosinopoiesis, potentially altering GC responsiveness at the progenitor level [31].

Evidence indicates that the sensitivity of eosinophils to GC–induced apoptosis varies according to their activation and maturation status. Eosinophils primed with cytokines such as IL-5 exhibit reduced pro-apoptotic responses to GCs, whereas less activated or more immature eosinophils are more susceptible to GC-induced apoptosis [63,64].

In humans, the transcriptional response of eosinophils to GCs involves the regulation of genes related to apoptosis, migration, and receptor signaling; however, the magnitude and direction of these responses may differ depending on the activation or maturation context [65].

Although direct studies in eosinophils are lacking, evidence from other cell type (B cell) demonstrates that epigenetic patterns—including chromatin accessibility and histone modifications—change during cellular maturation and influence responsiveness to external stimuli [66]. Such epigenetic differences may determine which genes are accessible for GC-mediated regulation at each maturation stage. In eosinophils, it is plausible that cells at distinct stages of maturation display specific epigenetic landscapes, thereby modulating GC responses—potentially favoring eosinopoiesis in immature stages while promoting apoptosis in mature cells.

7. Clinical and Translational Implications of GC-Induced Eosinopoiesis in Asthma

The paradoxical capacity of GCs to both suppress airway inflammation and promote bone marrow eosinophil production has profound clinical and translational implications. Traditionally, asthma management focuses on reducing peripheral eosinophilic inflammation as a biomarker of disease control and treatment efficacy [Barnes, GINA]. However, failure to consider the GC-induced amplification of bone marrow eosinopoiesis may contribute to a misinterpretation of clinical biomarkers and complicate patient stratification, especially in severe or corticosteroid-resistant asthma phenotypes [3,8].

Most of the mechanistic data on GC-induced eosinopoiesis derive from murine models [43,67,68]. Direct experimental evidence of a therapeutic benefit from selectively blocking bone marrow eosinophil output in allergic asthma is lacking. Experimental manipulation of eosinophil output may yield divergent outcomes, as demonstrated by Zhang et al. [69], who showed that blocking eosinophil-derived CCL-6 exacerbated airway inflammation in a murine asthma model, underscoring the need for cautious interpretation of potential benefits.

Translationally, the extrapolation of murine data to human asthma must consider the distinct regulatory networks of eosinopoiesis. While murine models frequently show GC-induced expansion of bone marrow eosinophil progenitors during allergic inflammation, human data indicate both stimulatory and inhibitory effects depending on the cellular and cytokine milieu. This complexity underscores the need for targeted studies in patients to assess whether selective modulation of bone marrow eosinophil output could provide clinical benefit without compromising the anti-inflammatory effects of systemic GCs.

While a recent preclinical study [70] suggests that bone marrow regulation significantly influences tissue eosinophil profiles, the net clinical impact of restricting eosinophil output in asthma—particularly in patients already receiving GCs—remains unproven and requires future translational and clinical investigation. Moreover, any therapeutic approach aimed at reducing eosinopoiesis must take into account the broader roles of eosinophils in tissue homeostasis and immune regulation [65,68], as systemic depletion could have unintended effects.

This concept should therefore be regarded as a hypothesis-generating framework rather than a validated treatment strategy.

One critical issue is the potential role of bone marrow-primed eosinophil reservoirs in asthma relapse following corticosteroid withdrawal. While GCs suppress airway eosinophilia during treatment, the expanded pool of marrow-derived eosinophils remains poised for rapid mobilization upon allergen re-exposure, stress, or infection [5,6]. The further increase in bone marrow eosinopoiesis observed after GC withdrawal may reflect a rebound phenomenon, driven by the sudden removal of the inhibitory effects of GCs on peripheral eosinophil survival and trafficking. This withdrawal could lead to a transient surge in eosinopoietic signals from inflamed tissues, such as elevated IL-5 and eotaxin production, thereby amplifying bone marrow eosinophil output beyond the levels observed during GC administration. This phenomenon may underlie the clinical observation that some patients experience exacerbations after tapering corticosteroid therapy, despite achieving prior control [71,72,73,74,75].

The modulation of bone marrow responsiveness by environmental and infectious factors—such as exposure to Staphylococcal enterotoxins—raises concerns for patients with persistent airway colonization by bacteria known to produce superantigens [8]. These individuals may exhibit both steroid resistance at the airway level and enhanced systemic eosinopoiesis, complicating therapeutic responses.

The interplay between eosinopoietic cytokines, lipid mediators, and GCs also presents new therapeutic targets. Pharmacological agents that block key eosinopoietic pathways—such as anti-IL-5 monoclonal antibodies (e.g., mepolizumab, reslizumab), leukotriene receptor antagonists (e.g., montelukast), or iNOS inhibitors—may synergize with GCs to suppress both peripheral inflammation and central eosinophil production [50,62]. This dual targeting approach could help prevent rebound eosinophilia and improve long-term asthma control.

From a translational research perspective, understanding the bone marrow’s role as an immunological hub in asthma may lead to the development of new biomarkers of disease activity and treatment response. A growing body of evidence [76,77,78,79,80,81] suggests that the presence of eosinophil progenitors in the blood, derived from the bone marrow eosinopoietic response to GCs, may serve as a predictive and monitoring tool in asthma management. Quantification of circulating eosinophil progenitors, especially CD34+/IL-5Rα+ and CD34+/CCR3+ cells, has shown potential as a surrogate marker for bone marrow eosinopoietic activity. Elevated levels of these progenitors in peripheral blood may reflect a state of marrow priming, predisposing patients to exacerbations following corticosteroid tapering or environmental allergen exposure.

Furthermore, soluble mediators associated with eosinopoiesis (IL-5, eotaxin, and CysLTs) could be explored as biochemical biomarkers indicating active eosinopoiesis or impaired corticosteroid suppression. Integrating these measurements into clinical practice could enable individualized risk stratification, guiding the initiation or intensification of biologic therapies targeting eosinopoiesis (e.g., anti-IL-5, anti-IL-5R, or anti-IL-13 agents) [82,83,84].

Advancements in flow cytometric immunophenotyping now enable detailed characterization of eosinophil progenitor populations within the bone marrow. Trindade et al. [31] demonstrated that markers such as CD34, CD123, CD49d, and Siglec-8 allow for the differentiation of eosinophil precursors from other myeloid lineages in human bone marrow samples.

Recent advances in eosinophil biology highlight the existence of functionally distinct eosinophil subpopulations, each with unique transcriptional signatures and tissue-specific roles [16]. Classically, eosinophils have been viewed as terminal effector cells in Th2-mediated inflammation, but it is now evident that homeostatic eosinophils—found in tissues like the gastrointestinal tract and adipose tissue—play roles in immune regulation, tissue remodeling, and metabolic homeostasis [36].

In the context of asthma, this plasticity raises critical questions about whether all eosinophil subsets respond uniformly to GCs. Preliminary evidence suggests that inflammatory eosinophils (E2 Eosinophils; characterized by higher IL-5Rα and Siglec-F expression in mice) may be more sensitive to GC-induced apoptosis than their homeostatic counterparts (E1 Eosinophils) [16,85]. Furthermore, it remains to be determined whether GCs preferentially expand specific eosinophil precursor subsets within the bone marrow, contributing to phenotypic diversity in the periphery. Current research does not provide strong evidence that GCs directly induce a specific eosinophil phenotype, but GCs can upregulate certain surface proteins, such as the glucocorticoid-induced TNF receptor, which may modulate eosinophil activation and cytokine secretion [86], although this does not equate to a clear E1/E2 or inflammatory/resident phenotype switch.

All this advocates for a paradigm shift in asthma research and management, emphasizing not only the control of airway inflammation but also the modulation of systemic hematopoietic processes. Incorporating this knowledge into clinical practice may inform better risk stratification, personalized therapy, and the development of novel interventions targeting the immunoendocrine axis.

To facilitate the translation of the concepts discussed into clinical practice,

Table 1. Summary of Key Clinical and Translational Considerations in GC-Induced Eosinopoiesis.

Key Biomarkers	Blood eosinophil count	Widely used in clinical practice for asthma phenotyping and monitoring treatment response.
	Bone marrow eosinophil progenitors (CD34+/IL-5Rα+)	Progenitor quantification can indicate bone marrow eosinopoietic activity.
	Surface activation markers (Siglec-8, CCR3)	Markers linked to chemotaxis and tissue recruitment.
	Glucocorticoid-induced TNF receptor expression	Possible link to eosinophil functional modulation under GC exposure.
	Transcription factor expression profiles (GATA-1, C/EBPε, PU.1)	Reflect lineage commitment and differentiation stage.
Risk Stratification Strategies	Baseline eosinophil levels pre-GC treatment	May help identify patients more likely to respond or relapse after GC therapy.
	Differential GC response based on maturation stage or activation state	Highlights importance of maturation stage in predicting GC efficacy.
Therapeutic Targets	IL-5/IL-5R signaling axis	Target for biologics such as mepolizumab; reduces eosinophil survival.
	STAT5 pathway in eosinopoiesis	Inhibition reduces GC-enhanced eosinopoiesis; potential strategy to limit side effects.
	GC receptor modulation	Modulation may affect both anti-inflammatory effects and eosinopoiesis.
	Autophagy-related pathways in eosinophil survival	Potentially linked to GC resistance in eosinophils.
Monitoring Approaches	Peripheral blood eosinophil counts during/after GC therapy	Simple and cost-effective monitoring tool.
	Flow cytometry of eosinophil progenitors	More specific assessment of bone marrow output to the periphery.
	Gene expression assays for GC-responsive genes	Provides insight into molecular response totherapy.

summarizes key biomarkers, risk stratification strategies, therapeutic targets, and monitoring approaches related to GC-induced eosinopoiesis. This synthesis is not intended as a prescriptive clinical guideline but rather as a conceptual framework for researchers and clinicians interested in integrating eosinophil biology into patient management.

8. Research Gaps in Glucocorticoid–Eosinopoiesis Interactions

The recognition that GCs can paradoxically enhance bone marrow eosinophil production challenges current paradigms in asthma management and opens new therapeutic frontiers. Instead of focusing solely on peripheral eosinophilic inflammation, future strategies must also address the central hematopoietic drive that sustains systemic eosinophilia, particularly in severe and corticosteroid-resistant asthma phenotypes.

From a translational standpoint, this understanding highlights two critical intervention points:

• 1—Blocking Bone Marrow Output:

Selective modulation of eosinopoietic pathways offers the potential to control eosinophil production at its source. While agents targeting IL-5 and IL-5Rα already reduce circulating eosinophils, upstream regulators such as STAT5, iNOS, and autophagy-related proteins (e.g., ATG5) represent novel targets for fine-tuning bone marrow eosinopoiesis. Additionally, modulating leukotriene signaling within the marrow niche remains an attractive avenue, especially given the established synergy between GCs and CysLTs in promoting eosinophil lineage commitment.

• 2—Interrupting Egress and Mobilization:

Beyond production, targeting the mechanisms that regulate eosinophil release from the marrow, such as VCAM-1/VLA-4 interactions and prostaglandin-mediated migratory cues, may help limit peripheral eosinophil loading without broadly impairing immune function.

Ultimately, future asthma therapies may need to integrate both peripheral anti-inflammatory actions and central hematopoietic control, using combination regimens that balance efficacy with safety. Importantly, the development of biomarkers reflective of marrow eosinopoietic activity—such as circulating progenitor profiles or soluble mediators—will be essential to personalize therapy and monitor treatment responses.

The emerging concept of “hematopoietic targeting in asthma” represents a promising paradigm shift, with the potential to reduce relapse rates, improve disease control, and offer new hope for patients with treatment-refractory eosinophilic asthma.

9. Future Research Directions

The dualistic role of GCs in asthma—potently suppressing peripheral eosinophilic inflammation while paradoxically promoting bone marrow eosinopoiesis—challenges the traditional, linear understanding of corticosteroid pharmacodynamics in allergic diseases. This systemic immunoendocrine paradox reflects an evolutionary adaptive mechanism whereby endogenous GCs mobilize hematopoietic reserves in response to physiological stressors, infection, or inflammation [6,9].

Emerging evidence underscores that GC-induced eosinopoiesis is not a passive byproduct of endocrine signaling, but rather a finely tuned, stage- and lineage-selective process, orchestrated through complex interactions with eosinopoietic cytokines, leukotrienes, prostaglandins, bone marrow stromal elements, and cytotoxic lymphocytes. Additionally, environmental and infectious factors can further amplify or dysregulate this response, with direct clinical consequences for steroid responsiveness and asthma control.

Clinically, this knowledge opens new avenues for asthma management, suggesting that therapeutic strategies should address both peripheral inflammation and central eosinophil production to prevent disease recurrence and corticosteroid resistance. Future research should aim to define specific biomarkers of bone marrow eosinopoietic activity and to develop targeted interventions capable of modulating this central hematopoietic axis without compromising the essential anti-inflammatory effects of GCs.

Although this review focuses on asthma, the mechanisms discussed regarding GC-driven eosinopoiesis and bone marrow priming have broader relevance. Conditions such as hypereosinophilic syndromes, eosinophilic granulomatosis with polyangiitis, and eosinophilic gastrointestinal disorders share overlapping pathways of eosinophil expansion and tissue infiltration [16].

Given that GCs remain the first-line therapy in many of these diseases [87], understanding their dualistic effects on eosinophil survival and production could inform therapeutic decisions across multiple eosinophil-associated pathologies. Additionally, emerging anti-eosinophilic biologics developed for asthma may also find application in these related conditions.

In summary, GCs exert a paradoxical dual effect on eosinophil biology, simultaneously reducing peripheral inflammation while potentially enhancing bone marrow eosinopoiesis. Although targeting the eosinopoietic component may represent a novel therapeutic avenue, the translational potential and clinical benefits of blocking GC-induced eosinopoiesis remain uncertain, particularly in human asthma, where most pathogenic features are driven by eosinophil recruitment, survival, and activation in the airways. The majority of evidence supporting this strategy comes from animal models, and further studies are needed to determine whether reducing bone marrow eosinophil output can provide meaningful clinical improvement without compromising the well-established anti-inflammatory benefits of GCs in peripheral tissues.