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30 September 2026

22 Pages

Inflammatory Biomarkers in Low Back Pain: Physiological Insights and Implications for Exercise: A Narrative Review

,
and
1
Department of Physiotherapy, University North, 42000 Varaždin, Croatia
2
Department of Physical Medicine and Rehabilitation, Clinical Hospital Sveti Duh, 10000 Zagreb, Croatia
*
Author to whom correspondence should be addressed.
Physiologia2026, 6(4), 58;https://doi.org/10.3390/physiologia6040058
This article belongs to the Section Exercise Physiology
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Abstract

Low back pain is a major cause of disability and is increasingly recognized as a multifactorial condition involving complex inflammatory and neuroimmune mechanisms. Inflammatory biomarkers may provide insight into the biological processes underlying pain persistence and may have potential value for patient stratification and treatment monitoring. This narrative review synthesizes current evidence on inflammatory biomarkers in low back pain and their potential pathophysiological relevance, with particular emphasis on the effects of exercise on inflammatory and neuroimmune responses. Literature searches were conducted in PubMed/MEDLINE and Google Scholar using combinations of terms related to low back pain, chronic low back pain, inflammatory biomarkers, cytokines, chemokines, neuroinflammation, sensitization, exercise, and physiotherapy, without publication-date restrictions. Relevant systematic reviews, meta-analyses, narrative reviews, observational studies, intervention studies, and selected mechanistic studies were considered based on their relevance to the review aims, methodological rigor, recency, and directness to low back pain populations. Among the most studied pro-inflammatory biomarkers are interleukins IL-1β, IL-6, IL-8, and IL-17; tumor necrosis factor-alpha (TNF-α); interferon-gamma (IFN-γ); C-reactive protein (CRP); and high-sensitivity C-reactive protein (hs-CRP). Commonly investigated anti-inflammatory cytokines include IL-4, IL-10, IL-13, and transforming growth factor-beta (TGF-β). Exercise is a cornerstone of conservative management for low back pain and may exert both pro- and anti-inflammatory effects, with responses depending on factors such as exercise type, intensity, duration, training status, and the tissues involved. However, the effects of exercise on inflammatory biomarkers in low back pain remain incompletely understood, and findings across studies are inconsistent. A better understanding of these relationships may provide insight into the biological effects of exercise and contribute to more individualized and biologically informed physiotherapy and exercise-based management of low back pain.

1. Introduction

Low back pain (LBP) is one of the leading causes of disability worldwide and represents a major public health challenge due to its high prevalence, recurrent nature, and substantial socioeconomic burden. It affects approximately 7–10% of the global population at any given time and is associated with reduced quality of life, impaired physical function, work absenteeism, and increased healthcare utilization [1]. Although symptoms resolve within a few weeks in most individuals, a proportion of patients develop pain that persists for more than three months and acquires the characteristics of chronic low back pain (CLBP) [2,3]. Accordingly, LBP is classified into acute, subacute, and chronic forms based on the duration of symptoms. Unlike acute LBP, which is often self-limiting, CLBP persists and frequently involves complex interactions among biological, psychological, and social factors [3,4]. This multifactorial nature has shifted contemporary understanding of LBP from a purely mechanical disorder toward a condition characterized by intricate neurophysiological and immunological mechanisms [5]. Increasing evidence indicates that LBP is associated with neuroinflammatory and immune responses involving both local spinal tissues and systemic pathways [6]. Tissue injury or degeneration may initiate inflammatory processes that contribute to nociceptor sensitization, altered neuronal excitability, and the development or maintenance of peripheral and central sensitization [7,8]. In this context, inflammatory biomarkers may provide insight into biological processes associated with pain persistence and neuroimmune dysregulation. Circulating inflammatory biomarkers have been investigated as potential indicators of immune and inflammatory processes associated with LBP [9,10,11]. However, findings across studies remain heterogeneous, with reported associations varying according to the biomarker examined, disease duration, and measurement context [10,11]. This variability complicates interpretation of their clinical relevance and highlights the importance of considering biomarker findings within their biological and clinical context. As most LBP is managed conservatively, particularly through physiotherapy and exercise-based interventions, understanding how exercise may influence inflammatory and neuroimmune responses is also of interest [9]. Recent publications have further addressed the relationship between exercise, LBP, and inflammatory biomarkers. Alonso-Sal et al. [10] systematically reviewed the effectiveness of physical activity in individuals with nonspecific LBP, including its effects on inflammatory biomarkers [10]. They concluded that, although exercise improves several clinical and functional outcomes, the available evidence remains insufficient to determine its effects on inflammatory biomarkers in nonspecific LBP [10]. More recently, Lo et al. [11] conducted a systematic review and meta-analysis involving participants with musculoskeletal pain. Their review included studies of several musculoskeletal conditions, including chronic and nonspecific LBP, and evaluated inflammatory markers such as CRP, IL-6, TNF-α, IL-1β, IL-8, and IL-10. The authors reported that exercise may influence inflammatory markers, although the included populations, exercise modalities, and biomarker outcomes were heterogeneous [11]. In addition, a recent systematic review and meta-analysis specifically examining inflammatory biomarkers in low back disorder and identified associations between several biomarkers, including IL-1β, IL-6, IL-8, MCP-1, IL-10, CTX-1, and hs-CRP, and clinical or treatment-related outcomes [12].
Beyond the more extensively studied inflammatory biomarkers, several emerging cytokines may also be relevant to the pathophysiology of LBP through their effects on intervertebral disc degeneration and inflammatory signaling. IL-33 has been implicated in the maintenance of intervertebral disc homeostasis, as its expression was reduced in degenerated nucleus pulposus tissue, while experimental IL-33 overexpression attenuated extracellular matrix degradation and apoptosis, partly through HIF-1α-associated mechanisms [13]. Similarly, IL-37, an anti-inflammatory member of the IL-1 family, was found to be reduced during intervertebral disc degeneration, and experimental supplementation attenuated cellular senescence and the expression of senescence-associated secretory phenotype factors through activation of the IL-1R8/NF-κB pathway [14]. IL-38 has also emerged as a potential regulator of disc-associated inflammation. Although IL-38 expression was increased in degenerated disc tissues, experimental treatment reduced TNF-α-induced inflammatory and matrix-degrading mediators, including IL-1β, IL-6, COX-2, MMP-13, and ADAMTS-5, through inhibition of NF-κB signaling [15]. Collectively, these findings suggest that IL-33, IL-37, and IL-38 may participate in mechanisms linking inflammatory signaling, extracellular matrix remodeling, and intervertebral disc degeneration [13,14,15]. However, current evidence is predominantly based on cellular and experimental studies, and further clinical studies are needed to determine their value as circulating biomarkers or clinically relevant therapeutic targets in patients with LBP. Importantly, recent studies have expanded the spectrum of potentially relevant biomarkers in LBP beyond commonly investigated inflammatory cytokines and acute-phase proteins. Therefore, associations have been reported for growth factors, adipose tissue-derived mediators, cytokines, and chemokines, further highlighting the heterogeneity of inflammatory and immune-related biomarker profiles in LBP [16,17,18,19]. This heterogeneity suggests that biomarker profiles may vary according to clinical phenotype, body composition, metabolic status, and other patient-related characteristics. Taken together, recent reviews demonstrate that the relationship between inflammatory biomarkers, exercise, and LBP has already been substantially investigated. The present narrative review therefore does not aim to reproduce these previous systematic syntheses. Rather, it adopts an integrative perspective by considering established and emerging inflammatory and inflammation-related biomarkers in relation to the pathophysiological mechanisms underlying LBP, including peripheral and central sensitization and neuroimmune signaling. Particular emphasis is placed on the potential immunomodulatory effects of exercise and on the context dependence of inflammatory responses, including the influence of exercise modality, intensity, duration, and individual characteristics on biomarker profiles. This approach is intended to complement existing evidence syntheses by linking biomarker findings with the biological mechanisms and exercise-related responses relevant to LBP.
Therefore, the aims of this narrative review are to: [i] provide an overview of the mechanisms linking inflammation and LBP; [ii] summarize the current evidence on key inflammatory biomarkers associated with LBP; and [iii] evaluate the potential effects of exercise on the inflammatory biomarkers.

2. Methods

This narrative review was conducted to synthesize the current evidence on inflammatory biomarkers in LBP, with particular emphasis on their potential pathophysiological relevance and the effects of exercise on inflammatory and neuroimmune responses. Literature searches were conducted in PubMed/MEDLINE and Google Scholar using combinations of terms related to low back pain, chronic low back pain, biomarkers, inflammatory biomarkers, cytokines, chemokines, neuroinflammation, central sensitization, peripheral sensitization, exercise, and physiotherapy. Boolean operators (AND, OR, and NOT) were used to combine search terms and broaden or refine the retrieval of relevant publications. No specific publication-date limits were applied, allowing the inclusion of both recent and relevant foundational studies. The final literature search was conducted on 2 July 2026, with no publication date restriction applied.
Studies were considered for inclusion when they investigated inflammatory or inflammation-related biomarkers in individuals with LBP, examined biological mechanisms linking inflammation and LBP, or evaluated the effects of exercise or exercise-based interventions on inflammatory biomarkers or related neuroimmune mechanisms. Relevant systematic reviews, meta-analyses, narrative reviews, observational studies, and intervention studies were considered. Studies were excluded when they were unrelated to LBP, did not address inflammatory or inflammation-related mechanisms relevant to the aims of the review, or did not provide sufficient information to support the synthesis.
Because this was a narrative rather than a systematic review, study selection was not based on a predefined protocol, and no formal risk-of-bias assessment or quantitative synthesis was performed. Evidence was prioritized according to its relevance to the review aims, methodological rigor, recency, and directness to LBP populations. Particular attention was given to the consistency or inconsistency of findings across studies, differences in LBP phenotype and duration, biomarker type and measurement context, and exercise characteristics such as modality, intensity, and duration.
The search and selection process were therefore designed to provide a transparent and clinically relevant synthesis of the available literature while preserving the narrative nature of the review.

3. Role of Inflammatory Biomarkers in the Pathophysiology of LBP

LBP is a multifactorial condition involving both nociceptive and neuropathic pain mechanisms. Numerous inflammatory biomarkers have been investigated in patients with LBP and are commonly classified into pro-inflammatory and anti-inflammatory mediators according to their biological function (Table 1). Among the most studied pro-inflammatory biomarkers are interleukin-1β (IL-1β), IL-6, IL-8, IL-17, tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), C-reactive protein (CRP), and high-sensitivity C-reactive protein (hs-CRP) [20]. The most commonly investigated anti-inflammatory cytokines include IL-4, IL-10, IL-13, and transforming growth factor-beta (TGF-β) [21]. Current evidence suggests that, rather than the concentration of an individual biomarker, the balance between pro-inflammatory and anti-inflammatory mediators is of greater importance [22,23].
Table 1. Summary of selected inflammatory and inflammation-related biomarkers and mediators in low back pain (data from references [24,25,26,27,28]).
Importantly, the inflammatory biomarker profile associated with LBP extends beyond the classical cytokines and acute-phase proteins. Observational studies from the Livshits research group have identified associations between LBP-related phenotypes and several less commonly investigated circulating factors [16,17,18,19]. In a large cross-sectional study, GDF-15, leptin, chemerin, and follistatin were elevated among individuals with LBP, although after adjustment for age, gender, body composition, and other covariates, GDF-15 remained independently associated with LBP-related disability [16]. Vaspin, an adipose tissue-derived serine protease inhibitor, has also been associated with several LBP-related pain and disability phenotypes, suggesting a possible link between adipose tissue biology, body composition, and musculoskeletal pain [17]. Further observational research demonstrated independent associations of GDF-15 and vaspin with radiographic features of facet joint osteoarthritis, while GDF-15 was also associated with lumbar disc degeneration, highlighting the potential relationship between circulating biomarkers and structural lumbar spine phenotypes [18]. More recently, vaspin has been investigated together with RANTES, IL-2, IL-17A, IL-4, and IL-10 in women with LBP undergoing lumbar traction therapy. The observed biomarker responses and their associations with clinical outcomes differed according to body mass index, suggesting that metabolic and adiposity-related factors may influence inflammatory and biomarker responses to treatment [19]. Collectively, these findings broaden the spectrum of potentially relevant biomarkers in LBP and emphasize that inflammatory profiles are heterogeneous and context-dependent rather than characterized by a uniform pattern.
Mechanistic and experimental evidence provides further insight into how local inflammation may contribute to LBP. Degenerative changes in spinal structures, particularly the intervertebral discs (IVDs), can activate nociceptors and trigger local inflammatory responses [28]. During intervertebral disc degeneration, dysregulated cytokine production, including alterations in IL-4, IL-6, IL-12, and IFN-γ, may contribute to changes in the inflammatory microenvironment, disruption of disc homeostasis, and progressive disc degeneration [29,30]. Furthermore, pro-inflammatory cytokines, particularly TNF-α and IL-1β, stimulate the production of nerve growth factor (NGF), thereby facilitating pathological nerve ingrowth into degenerated disc tissue and contributing to discogenic pain [31,32]. In disc herniation, inflammation, immune-cell infiltration, and neovascularization may further enhance nociceptive signaling and facilitate spontaneous disc resorption [33]. Resident disc cells and infiltrating immune cells can contribute to this inflammatory microenvironment by producing cytokines and chemokines that amplify inflammatory signaling [30]. These findings provide a mechanistic basis for a potential role of local inflammatory processes in the initiation and maintenance of nociception and peripheral sensitization.
Peripheral sensitization represents another mechanistic pathway linking local inflammation and tissue injury to the development and persistence of LBP. Mechanistic evidence on peripheral sensitization indicates that tissue injury can trigger the release of pro-inflammatory cytokines and algogenic mediators, including IL-1β, IL-6, TNF-α, NGF, bradykinin, substance P, prostaglandins, endogenous opioids, and glutamate, which may activate and sensitize peripheral nociceptors [34,35]. These mediators may lower the activation threshold of sensory neurons and increase their excitability, resulting in exaggerated responses to painful and, in some circumstances, normally non-painful stimuli [36]. Pro-inflammatory cytokines, particularly TNF-α and IL-1β, may also enhance neuronal excitability in the dorsal root ganglia, thereby increasing nociceptive signaling toward the spinal cord [37]. Persistent peripheral sensitization may consequently increase afferent nociceptive input and contribute to the development and maintenance of central sensitization in LBP [34].
Persistent nociceptive activity, local inflammation, and low-grade systemic inflammation may interact, potentially contributing to a bidirectional relationship between systemic inflammation and pain hypersensitivity [38]. Low-grade systemic inflammation (LGSI) is characterized by sustained, low-level activation of inflammatory pathways and increased circulating concentrations of inflammatory mediators, together with immune-cell activation, particularly macrophages [39]. Although LGSI generally does not cause overt tissue damage, circulating inflammatory mediators may exert systemic effects that extend beyond the local inflammatory environment [38]. Inflammatory mediators may also influence nociceptive processing and peripheral neuronal excitability through mechanisms involving peripheral nerve endings and dorsal root ganglia [40]. In this context, persistent inflammatory signaling may influence nociceptive processing beyond peripheral tissues and contribute to the development or maintenance of central sensitization, providing a plausible biological link between systemic inflammation, peripheral sensitization, and central sensitization [40].
Central sensitization is another proposed mechanism contributing to the persistence and chronification of LBP. Persistent nociceptive input and inflammatory signaling may contribute to enhanced responsiveness of central pain-processing networks, a process commonly referred to as central sensitization. In chronic LBP, this process may involve altered interactions between neurons and spinal glial cells, including microglia and astrocytes [20,41]. Experimental and mechanistic studies suggest that these neuroimmune interactions can modify synaptic transmission and nociceptive processing through the release or modulation of inflammatory and neuroactive mediators, including IL-1β, IL-6, TNF-α, IL-10, and BDNF [21,42,43]. BDNF is a neurotrophic factor rather than a classical inflammatory biomarker and may influence inhibitory neurotransmission and thereby facilitate sustained nociceptive signaling [44,45]. Thus, inflammatory and neuroimmune mechanisms may contribute to pain persistence not only through peripheral tissue responses but also through changes in central pain processing [46,47].
Overall, the available evidence suggests that local tissue inflammation, circulating inflammatory mediators, and altered nociceptive processing may act in concert during the persistence and chronification of LBP [46,47]. However, the contribution of individual inflammatory pathways is likely to vary across patients and clinical phenotypes, and mechanistic evidence should not be interpreted as establishing direct causal relationships between individual biomarkers and clinical outcomes.

4. Effects of Exercise on Inflammatory Biomarkers in LBP

Exercise is a cornerstone of conservative management for LBP and provides benefits beyond improvements in strength, flexibility, spinal stability, and physical function [11,48]. Evidence from exercise physiology and studies in healthy adults suggests that exercise can exert anti-inflammatory, immunomodulatory, and neurophysiological effects through changes in cytokine signaling, autonomic regulation, and endogenous pain modulation [11,24,48]. During exercise, skeletal muscle releases myokines and metabolites, including IL-6, BDNF, and lactate, which may participate in immune regulation and pain modulation [49,50]. Exercise-induced IL-6 may exert anti-inflammatory effects by stimulating anti-inflammatory mediators such as IL-10 and IL-1Ra and modulating pro-inflammatory cytokine signaling [49]. Increased blood flow during exercise may also facilitate tissue perfusion and influence nociceptive signaling [49,50]. These physiological mechanisms provide a biological rationale for the potential effects of exercise in LBP; however, evidence derived from exercise physiology or healthy populations should not be interpreted as direct evidence of therapeutic effects in patients with LBP. In patients with LBP, exercise has been associated with improvements in pain and physical function, although the extent to which these clinical effects are mediated by changes in inflammatory biomarkers remains uncertain [49,50].
Evidence from exercise physiology suggests that moderate-intensity exercise may promote an anti-inflammatory response, including modulation of pro-inflammatory cytokines such as TNF-α and IL-1β and increases in anti-inflammatory mediators such as IL-10 [49,51]. Whether these responses occur to the same extent in patients with LBP remains uncertain. In experimental and mechanistic studies, exercise has also been shown to modulate the activity and expression of nociceptive ion channels, including TRPV1 and Nav1.8, which may influence peripheral pain signaling [49,52]. Exercise-induced autonomic adaptations may additionally improve skeletal muscle perfusion and influence immune-cell activity through catecholamine-mediated mechanisms [49,51,52]. These metabolic, immune, vascular, and neurophysiological mechanisms provide plausible pathways through which exercise may influence peripheral sensitization and nociceptive input; however, much of the mechanistic evidence does not originate directly from LBP populations. In patients with LBP, these mechanisms may contribute to exercise-induced hypoalgesia, but their relative contribution to clinical improvement remains insufficiently established [49,51].
Evidence from exercise physiology and studies of musculoskeletal pain suggests that regular exercise may modulate inflammatory processes through immune regulation, reduction in oxidative stress, and stimulation of anti-inflammatory pathways [11,53]. However, the extent to which these effects translate into measurable changes in inflammatory biomarkers in patients with LBP remains uncertain [11,53]. The effects of exercise on inflammatory biomarkers may depend on exercise type, intensity, duration, training status, and individual characteristics, and evidence remains inconsistent regarding the optimal exercise modality for reducing inflammation and pain in LBP [54,55]. Various forms of exercise, including aerobic exercise, resistance training, and core stabilization, have been investigated for their effects on inflammatory cytokines (Table 2); however, evidence remains insufficient to determine which modalities provide the greatest anti-inflammatory or analgesic benefits in LBP [54,55]. Clarifying the relationship between exercise, inflammation, and clinical outcomes is therefore important for developing and optimizing physiotherapy strategies for individuals with LBP.
Table 2. Effects of Different Exercise Modalities on Inflammatory Biomarkers in LBP (data from references [24,26,49,50,55]).
Aerobic exercise has received particular attention because of its potential to improve physical function and alleviate pain in individuals with chronic LBP [56]. Evidence from exercise physiology and mechanistic research suggests that regular exercise may influence inflammatory processes through modulation of cytokine signaling, immune regulation, and metabolic pathways [57,58]. In patients with chronic LBP, a recent systematic review of non-pharmacological interventions reported changes in blood-based inflammatory biomarkers following exercise and other interventions, although the findings were heterogeneous and did not demonstrate consistent biomarker responses across interventions [24]. Similarly, a systematic review of inflammatory biomarkers in non-specific acute and chronic LBP reported associations between inflammatory markers, including IL-6, CRP, and TNF-α, and clinical characteristics such as pain and disability, while emphasizing substantial heterogeneity across studies [12]. These findings support a potential relationship between inflammatory processes and LBP but do not establish inflammatory biomarkers as direct mediators of exercise-related clinical improvement. Although TNF-α levels have been reported to decrease following some exercise interventions, responses may be less consistent than those observed for other inflammatory biomarkers [24]. Importantly, changes in inflammatory biomarkers should be interpreted as potential physiological adaptations associated with participation in an exercise programme rather than as evidence of a direct causal relationship between reduced inflammation and improvements in pain or quality of life. The observed changes may instead reflect one component of the broader physiological response to exercise, involving interconnected metabolic, immune, neuroendocrine, and cardiovascular adaptations [56,57,58].
Resistance training may exert its beneficial effects through both local mechanical adaptations and systemic physiological mechanisms [52]. By increasing the strength and functional capacity of trunk and lower-extremity muscle, resistance training can enhance dynamic joint stability, redistribute mechanical loads, and reduce excessive stress on joint structures, thereby contributing to pain reduction and improved joint function. In addition to these mechanical effects, skeletal muscle acts as an endocrine organ during and following exercise, releasing myokines into the circulation that can influence systemic immune, metabolic, and neurochemical processes [52]. Among these mediators, IL-6 increases acutely in response to resistance exercise and, within the context of exercise, may exert predominantly anti-inflammatory effects by stimulating the production of IL-10 and IL-1ra while suppressing pro-inflammatory cytokines such as TNF-α [53]. Repeated exercise sessions may consequently contribute to a reduction in basal inflammatory activity over time, promoting a more favorable anti-inflammatory environment that could help attenuate mechanisms involved in persistent nociceptive pain.
Motor control exercises and core stabilization training primarily target neuromuscular coordination, proprioception, and movement quality [26,49,55]. Although their direct effects on inflammatory biomarkers remain less extensively studied, improvements in movement efficiency and neuromuscular control may reduce mechanical loading and nociceptive input; whether these effects are accompanied by measurable changes in inflammatory biomarkers remains unclear.
Despite the increasing recognition of “exercise as medicine,” one of the major challenges to its standardized clinical implementation is the absence of consensus regarding the optimal exercise dose. The FITT framework (Frequency, Intensity, Time, and Type) provides a practical basis for exercise prescription; however, substantial heterogeneity in exercise protocols, participant characteristics, and outcome measures limits direct comparison across studies [54,55,59]. Moreover, differences in pain phenotypes suggest that a uniform exercise prescription may not be appropriate for all individuals with chronic LBP. Future physiotherapy strategies may therefore benefit from a more individualized and stratified approach, potentially incorporating objective biomarkers, to identify patients who are most likely to respond to specific exercise modalities. Finally, much of the existing evidence continues to rely predominantly on subjective, self-reported clinical outcomes. Future research should strengthen the investigation of the relationship between clinical improvements and objective biological changes to determine whether exercise-induced alterations in inflammatory biomarkers are mechanistically linked to reductions in pain and improvements in function.

5. Diagnostic and Prognostic Potential of Inflammatory Biomarkers in LBP

One of the major challenges in managing LBP is its considerable heterogeneity. Patients with similar clinical presentations may have different underlying mechanisms, including disc degeneration, peripheral inflammation, central sensitization, neuropathic pain, psychosocial factors, and metabolic dysfunction [25]. In this context, inflammatory biomarkers may help characterize biological features that are not readily captured by conventional clinical assessment. Several studies have reported elevated circulating levels of IL-6, TNF-α, IL-1β, IL-8, monocyte chemoattractant protein-1 (MCP-1), and high-sensitivity C-reactive protein (hs-CRP) in subsets of patients with LBP compared with asymptomatic controls [25,26,27]. These findings suggest that LGSI may be involved in LBP in some individuals. However, substantial overlap in biomarker concentrations between patients and healthy individuals limits the diagnostic utility of individual biomarkers [25,27]. Therefore, inflammatory biomarkers are better considered complementary measures rather than standalone diagnostic tests. Their integration with clinical assessment, imaging, functional measures, and patient-reported outcomes may provide a more comprehensive characterization of LBP. Furthermore, multiplex biomarker panels combining several cytokines and chemokines may have greater potential than individual biomarkers by reflecting the complexity of inflammatory and neuroimmune pathways [25,27].
Beyond their association with LBP, inflammatory biomarkers have also been investigated for their potential prognostic value. Prognostic biomarkers would be expected to provide information about future clinical outcomes, such as symptom persistence, disability, functional recovery, or treatment response. Elevated baseline levels of several pro-inflammatory cytokines have been associated with greater pain intensity, increased disability, and prolonged symptoms in some longitudinal studies [27,60]. IL-6 has been among the most consistently investigated biomarkers, with higher concentrations associated with persistent pain and poorer physical functioning [27,60]. Similarly, elevated TNF-α and IL-1β have been associated with greater pain severity and may be related to processes involved in intervertebral disc degeneration [27,60]. Chemokines such as MCP-1 and IL-8 have also been investigated as potential indicators of persistent inflammatory and neuroimmune activity; however, their prognostic value remains insufficiently established [27,60]. Increased hs-CRP concentrations may be associated with greater disability and persistent symptoms, particularly in individuals with metabolic risk factors [24,25]. In contrast, anti-inflammatory mediators such as IL-10 may have potential protective or prognostic relevance, with lower concentrations potentially reflecting impaired resolution of inflammation [25,26,60]. However, these associations should not be interpreted as evidence that individual biomarkers are validated prognostic markers, as prospective validation and demonstration of clinically meaningful predictive performance remain limited (Table 3).
A related but distinct concept is the potential use of biomarkers for patient stratification. Rather than predicting clinical outcomes independently, biomarkers may represent candidate research tools for identifying biologically distinct patient subgroups that may differ in underlying mechanisms or treatment responses. The balance between pro-inflammatory and anti-inflammatory mediators, as well as multiplex biomarker profiles, may therefore provide greater information for characterizing biological phenotypes than the concentration of a single biomarker [61]. Such profiles could potentially be investigated in combination with clinical, functional, imaging, metabolic, and psychosocial characteristics to define biologically and clinically relevant patient subgroups and explore their potential relevance to individualized management. However, biomarker-based stratification currently remains a research concept rather than an established clinical approach. Substantial variability between studies and the influence of factors such as age, gender, obesity, smoking, sleep, psychological stress, physical activity, medication use, and comorbidities currently limit the development and clinical applicability of biomarker-based prognostic or stratification models. Robust prospective validation is required to determine whether biomarker-informed stratification can improve treatment selection or clinical outcomes in LBP.
Table 3. Summary of the main findings.

6. Discussion

The present review synthesizes current evidence on the role of inflammatory biomarkers in the pathophysiology of low back pain and the mechanisms through which exercise may modulate inflammatory processes. Overall, the most consistent evidence indicates that inflammatory and neuroimmune processes are associated with LBP, although the strength and nature of these associations vary across LBP phenotypes and biomarker contexts [24,27]. Inflammatory mediators and inflammation-related biomarkers, including IL-1α, IL-1β, IL-6, TNF-α, IL-17, IL-8, MCP-1, and hs-CRP, have been implicated in these processes, whereas neurotrophic factors such as NGF and BDNF may contribute to nociceptive signaling, neuroplasticity, and pain modulation [24,27,50,63]. IL-10 and TGF-β contribute to immune regulation and tissue repair [25,27,49,61]. Although altered biomarker profiles have been associated with pain, disability, and impaired physical function, their clinical application remains limited. The often-limited relationship between imaging findings and clinical symptoms further supports a multidimensional biopsychosocial and neuroimmune model of LBP, in which structural, inflammatory, neurological, psychological, and lifestyle-related factors interact [27,56].
Persistent inflammatory signaling may contribute to extracellular matrix degradation, nociceptor sensitization, glial activation, and altered pain modulation, potentially sustaining pain beyond the initial tissue injury [48,51]. In several LBP populations, IL-6 and TNF-α have been associated with greater pain severity and disability [11,48,51]. Importantly, IL-6 illustrates the context-dependent nature of cytokine activity: chronic inflammatory IL-6 may contribute to pain sensitization, whereas transient IL-6 released by contracting skeletal muscle during exercise acts primarily as a myokine and promotes anti-inflammatory pathways involving IL-10 and IL-1Ra [49,61]. Similarly, IL-1α and IL-1β are important pro-inflammatory mediators involved in the inflammatory response associated with tissue injury and degeneration and may contribute, together with TNF-α, to matrix degradation and neuroinflammatory processes [49].
No single biomarker is likely to adequately capture the biological complexity of LBP because inflammatory mediators operate within interconnected and highly regulated networks [58,61]. Multibiomarker signatures, potentially combined with clinical, imaging, functional, and psychosocial characteristics, may provide greater value for characterizing biologically distinct patient subgroups than isolated biomarkers. These approaches may serve as candidate research tools for potential patient stratification and could be investigated for their relevance to tailoring exercise or physiotherapy interventions. However, biomarker-informed stratification currently remains a research hypothesis rather than an established clinical approach. Prospective validation is required to determine whether such approaches can reliably identify clinically meaningful subgroups and ultimately improve treatment selection or clinical outcomes.
The evidence that exercise modifies inflammatory biomarkers in LBP is promising but remains uncertain. Exercise represents an important component of conservative management and may also exert immunomodulatory effects by regulating cytokine production, immune-cell activity, neuroinflammation, endogenous pain inhibition, and adaptive neuroplasticity [49,58]. Skeletal muscle-derived myokines, particularly exercise-induced IL-6, may stimulate IL-10 and IL-1Ra and suppress TNF-α, while repeated exercise may reduce basal pro-inflammatory activity, oxidative stress, and NF-κB signaling [49,50]. However, effects on inflammatory biomarkers remain heterogeneous and may depend on exercise modality, intensity, frequency, duration, adherence, and participant characteristics. Aerobic and combined aerobic-resistance exercise have shown potential beneficial effects on systemic inflammatory markers such as hs-CRP, TNF-α, and IL-6, although findings are not consistent across studies, and evidence for motor control and other physiotherapy approaches remains less conclusive [50,56,59].
Importantly, recent evidence indicates that clinical improvements following exercise do not necessarily coincide with measurable changes in circulating inflammatory biomarkers. Gollan et al. reported that a 12-week run–walk intervention in adults with chronic LBP improved pain outcomes, but did not result in significant between-group changes in circulating CRP, TNF-α, or IL-8 [60]. Moreover, changes in these inflammatory markers were not associated with changes in pain intensity or mental health outcomes [60]. These findings highlight the complex relationship between exercise, systemic inflammation, and clinical outcomes and suggest that commonly measured peripheral inflammatory biomarkers may not fully capture the biological mechanisms underlying exercise-related improvements in chronic LBP. The absence of detectable changes in circulating biomarkers should therefore not necessarily be interpreted as an absence of biological effects of exercise, particularly given the multifactorial nature of chronic LBP.
The optimal exercise dose for clinically meaningful immunological adaptations has also not been established. Interpretation of the evidence is further limited by small sample sizes, heterogeneous patient populations, and inconsistent control of confounding factors, including age, gender, body mass index, metabolic status, smoking, physical activity, psychological stress, sleep, medication use, and comorbidities [61]. Consequently, biomarker-guided physiotherapy remains a promising but largely investigational approach. Current evidence therefore supports considering inflammatory biomarkers primarily as adjunctive research measures and potential candidates for patient stratification, rather than as validated standalone diagnostic, prognostic, or treatment-selection tools.
Future research should prioritize standardized biomarker assessment, adequately powered longitudinal studies, comprehensive multi-biomarker panels, and biomarker-guided exercise trials. Such approaches may clarify whether exercise-induced changes in inflammatory biomarkers are mechanistically related to improvements in pain and function and may ultimately support more individualized physiotherapy strategies for LBP.
Several limitations of the present review should be acknowledged. First, this was a narrative review rather than a systematic review or meta-analysis; therefore, study selection was not based on a predefined protocol, formal risk-of-bias assessment, or quantitative synthesis, and potential reference selection bias cannot be completely excluded. Second, the evidence synthesized in this review was heterogeneous with respect to study populations, pain phenotypes, clinical characteristics, and biological outcomes, and some mechanistic conclusions were based on indirect evidence from healthy populations, other musculoskeletal conditions, or experimental studies rather than directly from patients with LBP. Therefore, findings from these populations may not be directly generalizable to LBP. Third, substantial analytical heterogeneity exists among biomarker studies, including differences in biological specimens, sampling conditions, assay methods, assay sensitivity, and timing of biomarker measurement, which may contribute to variability in reported biomarker concentrations and limit direct comparisons between studies. Fourth, many studies were observational or cross-sectional and did not adequately account for potential confounding factors such as age, gender, body mass index, smoking, physical activity, sleep, psychological stress, medication use, and comorbidities. Consequently, residual confounding cannot be excluded and causal relationships between inflammatory biomarkers, pain, and functional outcomes cannot be established. Finally, although exercise appears to influence inflammatory biomarkers, substantial heterogeneity in exercise modality, intensity, frequency, and duration, together with limited LBP-specific evidence, means that the optimal exercise dose required to induce clinically meaningful biological adaptations remains uncertain.

7. Future Directions

Despite increasing evidence that exercise may modulate inflammatory processes, several important questions remain unresolved. Future studies should establish the optimal exercise dose and modality for clinically meaningful biomarker changes, develop standardized protocols for biomarker assessment, and identify patient subgroups most likely to respond to specific physiotherapy interventions. Longitudinal studies integrating inflammatory biomarkers with neuroimaging, quantitative sensory testing, genetic and digital health measures may further clarify the mechanisms underlying exercise-induced changes in LBP. Particular attention should also be given to multibiomarker profiles and their potential role in patient stratification and individualized exercise prescription. Overall, exercise should be viewed not only as a mechanical intervention but also as a potential biological regulator of immune and neuroimmune processes. Further research is needed to determine whether these biological adaptations are directly associated with improvements in pain and function and whether they can be translated into more precise and individualized physiotherapy strategies for patients with LBP.

8. Conclusions

LBP is increasingly understood as a multidimensional condition involving interactions among inflammation, peripheral and central sensitization, neuroimmune processes, and maladaptive neuroplasticity. Inflammatory biomarkers may provide important insights into the biological heterogeneity of LBP and have potential value for patient stratification, prognostic assessment, and monitoring treatment response, although no single biomarker currently has sufficient specificity or diagnostic accuracy for routine clinical use. Exercise represents not only a mechanical intervention but also a potential modulator of inflammatory and neuroimmune pathways, influencing cytokine signaling, neuroinflammation, endogenous pain modulation, and adaptive neuroplasticity. These biological responses provide plausible mechanisms through which exercise may influence pain and function; however, current evidence does not establish that modulation of inflammatory or neuroimmune pathways is responsible for the clinical benefits of exercise. Further research using standardized methodologies, longitudinal designs, and multidimensional biomarker profiles is needed to determine the relationship between exercise-induced biological changes and clinical outcomes and to establish whether inflammatory biomarkers can contribute to more individualized and evidence-based physiotherapy strategies for patients with LBP.

Author Contributions

M.F., M.B. and M.J.Đ. contributed equally in the conceptualization, writing and editing of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

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