Search Results (1,068)

Gout is a prototypical sterile inflammatory disease caused by the deposition of monosodium urate (MSU) crystals in joints and periarticular tissues. Although acute gout flares are characterized by rapid and intense neutrophil-dominated inflammation, they often resolve spontaneously, suggesting that neutrophils may contribute not only to inflammatory amplification but also to endogenous resolution. In this review, we summarize current evidence on the multifaceted roles of neutrophils in gout across different stages of disease. We discuss how MSU crystals activate innate immune signaling and promote neutrophil recruitment, activation, and effector responses, thereby driving acute inflammation. We further examine the diverse neutrophil programs involved in gout, including apoptosis, necroptosis, pyroptosis, autophagy, efferocytosis, and NET release. Particular attention is given to the dual roles of NETs in gout, as they can both amplify inflammation and, in their aggregated form, facilitate cytokine degradation, crystal sequestration, and inflammation resolution. In addition, we address the potential contribution of neutrophil-derived extracellular vesicles and neutrophil-associated mechanisms to tophus formation and chronic disease progression. By integrating recent advances and ongoing controversies, this review highlights neutrophils as dynamic regulators of both inflammatory injury and resolution in gout, and underscores their potential as therapeutic targets in immune-mediated crystal inflammation. Full article

Non-marneffei Penicillium species are ubiquitous molds usually dismissed as contaminants in respiratory cultures; invasive disease is rare and may mimic malignancy, tuberculosis, or sarcoidosis. A 39-year-old apparently immunocompetent man with asthma, a smoking history, and tuberculosis exposure presented with chronic cough, fever, night sweats, and weight loss. Chest computed tomography (CT) showed right lower-lobe subpleural consolidation, bilateral nodules, and mediastinal lymphadenopathy. Sputum and bronchoalveolar lavage (BAL) studies for tuberculosis were repeatedly negative; CT-guided lung biopsy showed a non-necrotizing granuloma, suggesting sarcoidosis. Five months later, the original lesions had regressed, and new contralateral pleural-based nodules appeared, establishing a migratory pattern. Repeat BAL grew a Penicillium species, a second recovery after an earlier isolate was dismissed as contamination. Surgical mediastinal lymph-node biopsy showed necrotizing granulomatous inflammation containing PAS- and GMS-positive septate hyphae, establishing proven invasive fungal disease, and fungal culture of the same tissue grew a Penicillium species; HIV and hepatitis serologies were negative. Liposomal amphotericin B followed by oral voriconazole produced near-complete radiological resolution. Attribution to Penicillium rests on recovery of the mold from the surgical tissue itself; identification nevertheless remained at genus level, because molecular identification, susceptibility testing, and fungal biomarkers were unavailable, and invasion of lung parenchyma was never demonstrated histologically. Migratory infiltrates should prompt reconsideration of fixed diagnoses; repeated mold recovery with tissue-invasive hyphae and treatment response warrants reassessment rather than dismissal as contamination. Full article

Nasal polyposis is a multifactorial disorder arising from complex interactions among cellular, molecular, and inflammatory mechanisms. The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and other ion channels are essential for epithelial ion transport, mucosal hydration, and barrier integrity in the nasal airway. Prostaglandin E₂ (PGE₂) acts not only as an inflammatory mediator but also as a regulator of ion exchange through CFTR-dependent and CFTR-independent pathways. Ionocytes, specialized epithelial cells that regulate ion balance and fluid secretion in the respiratory tract, are closely associated with CFTR function. Both eosinophilic and non-eosinophilic inflammation may alter ionocyte abundance and function, thereby reducing normal CFTR activity. Chronic rhinosinusitis with nasal polyps (CRSwNP) is also characterized by diminished PGE₂ production. The I³PGE₂ hypothesis proposes that CRSwNP results from the combined effects of ion channel dysfunction, persistent inflammation, altered ionocyte number and function, and impaired PGE₂ synthesis. Together, these abnormalities disrupt nasal physiology and promote polyp formation. We hypothesize that corticosteroids and biologic therapies may improve CRSwNP by reducing inflammation, restoring ion channel activity, improving ionocyte function, and recovering PGE₂ production. These effects enhance hydration and mucociliary clearance, limit mucus accumulation, restore epithelial homeostasis and mucosal host defense, and ultimately contribute to the reduction or resolution of nasal polyps. Full article

Objective: This study established a rat model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) to evaluate pathological damage, collagen deposition, inflammatory cytokine levels, and key gene/protein expression following Hedyotis diffusa water extract (HDWE) intervention. Combined with ultra-high-performance liquid chromatography-quadrupole Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS), transcriptomic analysis, and molecular simulation, this study identified the bioactive components of HDWE, evaluated their potential interactions with ALI-related targets, and explored the multi-omics-based protective mechanisms of HDWE. Methods: Thirty-six Sprague–Dawley (SD) rats were randomly divided into six groups: Control group, ALI group, DXMS group, HDWE-L group (100 mg/kg), HDWE-M group (200 mg/kg), and HDWE-H group (300 mg/kg). Hematoxylin and eosin (H&E) and Masson’s trichrome staining were used to evaluate lung pathological changes and collagen deposition. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum tumor necrosis factor-α $\mathrm{T}\mathrm{N}\mathrm{F}-\mathsf{\alpha }$ interleukin-1β $\mathrm{I}\mathrm{L}-1\mathsf{\beta }$, erleukin-6 (IL-6), and interleukin-10 (IL-10) levels. Transcriptomic analysis identified differentially expressed genes (DEGs), followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), receiver operating characteristic (ROC), and immune infiltration analyses. Quantitative real-time polymerase chain reaction (qRT-PCR) detected the mRNA expression levels of SPHK1, RELA, and NFKBIA. Immunohistochemistry evaluated the expression of eight hub targets, including endothelin-1 (EDN1), sphingosine kinase 1 (SPHK1), intercellular adhesion molecule 1 (ICAM1), interleukin-17 (IL-17), prostaglandin-endoperoxide synthase 2 (PTGS2/COX-2), NF-κB p65 (encoded by RELA), WT1-associated protein (WTAP), and myeloperoxidase (MPO). UHPLC-Q-Orbitrap HRMS characterized HDWE constituents. Molecular docking analysis was performed between 22 compounds and eight hub targets, followed by 100 ns molecular dynamics simulations and molecular mechanics-Poisson–Boltzmann surface area (MM/PBSA) binding free energy calculations for five core targets. Compared with the control group, the ALI group showed increased levels of TNF-α (86%), IL-1β (107%), and IL-6 (66%), accompanied by a 43% reduction in IL-10 and a 300% increase in lung collagen deposition. All HDWE doses alleviated inflammatory responses, with medium-dose HDWE showing the most pronounced effects. Specifically, medium-dose HDWE increased IL-10 levels by 52% and reduced IL-6, TNF-α, and IL-1β levels by 18%, 22%, and 11%, respectively. Transcriptomic analysis identified 2512 DEGs between the control group and ALI groups, 832 exclusive DEGs between the ALI group and HDWE-M groups, and 876 overlapping DEGs enriched in TNF, IL-17, and NF-κB signaling pathways. The eight-hub-gene diagnostic model achieved an area under the curve (AUC) of 0.969. RELA, SPHK1, and four other hub genes showed positive correlations with Th1, Th17, and neutrophil infiltration. In the ALI group, SPHK1, RELA, and NFKBIA mRNA expression levels were 1.30-, 0.96-, and 0.71-fold of those in the control group, respectively. Compared with the ALI group, high-dose HDWE treatment and low-dose HDWE treatment reduced SPHK1 expression to 0.62- and 0.57-fold, respectively, and increased NFKBIA expression to 1.68- and 1.58-fold, respectively. High-dose HDWE treatment reduced RELA expression to 0.43-fold. The expression levels of inflammation-related proteins were increased in the ALI group and were reduced after HDWE treatment. Twenty-two HDWE components were identified, 16 of which met the docking criteria. Asperulosidic acid exhibited favorable predicted binding affinities with all eight targets, with calculated binding free energies of −14.74, −14.92, −17.58, −23.04, and −16.10 kcal/mol for MPO, IL-17, NF-κB p65, PTGS2/COX-2, and SPHK1, respectively. Conclusions: This study provides systematic in vivo pharmacodynamic and in silico component-target evidence regarding the protective effects of HDWE against LPS-induced ALI. HDWE treatment increased NFKBIA expression and reduced SPHK1, RELA, and multiple inflammatory protein levels, suggesting that HDWE may regulate the IL-17/NF-κB-associated inflammatory network, although direct causal relationships require further validation. Asperulosidic acid may represent a key bioactive component with broad target-binding potential. This study was limited by the use of an LPS-induced rat ALI model without gene knockout or target inhibitor validation; therefore, further functional experiments are required to confirm the proposed regulatory mechanisms. Full article

Background: Osteoporosis is a multifactorial skeletal disorder characterized by reduced bone mass, impaired bone remodeling, and an increased risk of fractures, particularly under estrogen-deficient conditions. Artocarpus integer (Thunb.) Merr. contains prenylated flavonoids and chalcone derivatives with diverse biological activities; however, its anti-osteoporotic potential remains largely unexplored. This study investigated the phytochemical composition, molecular mechanisms, and anti-osteoporotic effects of A. integer leaf extract in an ovariectomized (OVX) rat model. Methods: Phytochemical profiling was performed using liquid chromatography–high-resolution mass spectrometry (LC–HRMS). Network pharmacology was employed to identify potential osteoporosis-related targets and signaling pathways. The anti-osteoporotic activity of the extract was evaluated in OVX rats through physiological and biochemical assessments, including body weight gain, uterine weight, serum biomarkers, femoral calcium content, and RT-PCR analysis of genes associated with osteogenesis, osteoclastogenesis, and estrogen signaling. Results: LC–HRMS analysis identified several bioactive compounds, including isobavachalcone, artocarpesin, morachalcone A, genistein, apigenin, luteolin, naringenin, catechin derivatives, and mangiferin. Network pharmacology revealed 96 overlapping targets between A. integer phytochemicals and osteoporosis-related genes, highlighting pathways involved in estrogen signaling, PI3K–Akt signaling, osteoclast differentiation, inflammation, and metabolic regulation. In vivo, OVX rats exhibited increased body weight gain, uterine atrophy, elevated leptin levels, reduced adiponectin concentrations, and decreased femoral calcium content. Treatment with A. integer attenuated OVX-induced metabolic alterations, improved adipokine profiles, and increased femoral calcium content, particularly in the medium-dose group. RT-PCR analysis demonstrated the upregulation of the osteogenic markers Runx2 and Osx, together with the downregulation of the osteoclastogenic markers TRAP. Conclusions: Artocarpus integer leaf extract exhibited promising anti-osteoporotic activity through the coordinated regulation of osteogenesis, osteoclastogenesis, estrogen-related signaling, and bone mineral preservation. These findings support the potential development of A. integer as a nutraceutical candidate for the prevention or management of postmenopausal osteoporosis. Full article

Emphysema is a chronic lung disease characterized by irreversible alveolar destruction, with distinct imaging subtypes—centrilobular emphysema (CLE), panlobular emphysema (PLE), and paraseptal emphysema (PSE). The cellular and molecular mechanisms driving subtype-specific pathogenesis remain poorly understood. Here, we performed single-cell RNA sequencing on emphysematous lung tissues from nine patients (three per subtype) to map the transcriptional landscape across CLE, PLE, and PSE. Profiling 84,704 high-quality cells, we identified eight major cell types, and subsequent subclustering uncovered subtype-enriched populations and transcriptional features. CLE was characterized by upregulated inflammatory pathways in ciliated cells and activated macrophage–epithelial/fibroblast crosstalk, suggesting an airway-derived infection and inflammatory phenotype. In PLE, the proportions of Natural Killer T (NKT) cells and Group 1 innate lymphoid cells (ILC1s) with enhanced cytotoxicity were increased, and mesothelial cells showed upregulation of extracellular matrix (ECM)-related genes, indicating dysfunction in innate immune cells and abnormal repair of mesothelial cells. PSE showed pronounced ECM remodeling signatures, with an increased proportion of systemic venous endothelial cells and enhanced fibroblast–epithelial interactions. Collectively, our findings reveal that CLE is predominantly driven by airway-originated inflammation, PSE exhibits a fibrosis-like remodeling phenotype, and PLE represents an intermediate state of innate immune activation and matrix dysregulation, providing a single-cell resolution framework for subtype-specific therapeutic targeting. Full article

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) remains a challenging complication of bisphosphonate therapy because jaw extraction sockets exposed to bisphosphonates represent impaired wound environments rather than ordinary bone defects. This narrative review summarizes clinical, cellular, animal, and biomaterial evidence on the mechanisms that limit BRONJ repair and discusses how these pathological barriers can inform local material design. Current evidence suggests that BRONJ repair is constrained by impaired osteoclast-mediated remodeling, osteocyte and osteoblast dysfunction, oxidative stress, unresolved inflammation, angiogenic insufficiency, microbial challenge, mucosal instability, and changes in bone material properties. Biomaterial strategies investigated to date include local delivery of regenerative factors, restoration of remodeling activity, extracellular vesicles, nucleic acid nanostructures, platelet-derived matrices, antibacterial and ion-releasing hydrogels, angiogenic or lymphangiogenic systems, and mechanically adaptive scaffolds. Most studies remain preclinical and are based on rodent extraction or mandibular defect models, and few establish a direct causal link between a specific material property and durable BRONJ resolution. Future materials should be judged not only by their ability to enhance bone formation, but also by whether they can re-establish a sealed, vascularized, immune-balanced, and remodeling-competent socket capable of sustained jawbone repair. Full article

Sterile inflammation in the course of myocardial infarction can be a factor contributing to cardiac remodeling and heart failure. To break this pathological vicious circle, the polarization of macrophages to a reparative M2 phenotype, to start the tissue repair process and alleviate the inflammation, is the key. Recent studies have shown that the nuclear receptor subfamily 4 group A (NR4A) orphan nuclear receptor family, particularly nuclear receptor subfamily 4 group A member 1 (NR4A1/NUR77), plays a role in macrophage reprogramming in relation to the modulation of macrophage polarization. Herein, we discuss in detail the specific pathways regulated by NR4A receptors during cellular reprogramming, including the nuclear factor kappa B (NF-κB) pathway and the oxidative phosphorylation pathway. We list below the beneficial effects of NR4A-treated macrophages in the hypoxic cardiac tissue, including their essential contribution to the formation of a neovascular network, the maintenance of the extracellular matrix by fibroblasts, and the direct rescue of remaining cardiomyocytes. In addition, given the translational potential of targeted therapy with immunomodulatory molecules against NR4A, we also review the design of macrophage-specific nanodelivery systems and the creation of novel small-molecule activators for ischemic cardiovascular diseases to identify therapeutic targets for cardiac repair based on NR4A. Full article

Background: Mycobacterium marinum is a slow-growing nontuberculous mycobacterium associated with aquatic environments and may cause chronic skin and soft-tissue infections following minor skin trauma. Diagnosis can be delayed because clinical manifestations may mimic conventional bacterial infections. We report an unusual case in a kidney transplant recipient with a positive QuantiFERON-TB Gold test and subsequent M. marinum infection of the hand. Case presentation: A 53-year-old man with a history of kidney transplantation and long-term immunosuppressive therapy developed progressive swelling, pain, erythema, and functional impairment of the right third finger. After independently discontinuing tacrolimus, mycophenolate mofetil, and prednisone following a positive QuantiFERON-TB Gold test, he developed a progressive hand infection despite empirical ciprofloxacin therapy. He reported repeated exposure to a domestic freshwater aquarium and frequent contact with aquarium water and filtration equipment, with minor skin abrasions. Surgical exploration revealed dense, whitish, caseous-appearing material. Histopathology demonstrated chronic granulomatous inflammation, while Ziehl–Neelsen staining showed acid-fast bacilli. Culture yielded slow-growing photochromogenic colonies at 28–32 °C, and species-specific PCR confirmed M. marinum. No antimicrobial susceptibility testing was performed. Following surgical drainage and six days of empirical ciprofloxacin, no targeted antimycobacterial therapy was administered. The patient achieved complete clinical resolution, and immunosuppressive therapy was gradually reintroduced approximately four weeks after surgery. Conclusions: This case highlights the importance of considering M. marinum in persistent or treatment-refractory hand infections, particularly in patients with aquarium exposure and impaired immunity. Early tissue sampling, appropriate culture conditions, and molecular identification are essential for diagnosis. A positive QuantiFERON-TB Gold result should be interpreted cautiously because cross-reactivity with M. marinum is possible. The favorable outcome observed after surgical source control and a short empirical course of ciprofloxacin is unusual and should not be interpreted as evidence supporting short-course monotherapy for deep M. marinum infection. Because antimicrobial susceptibility testing and serial follow-up cultures were unavailable, the contribution of ciprofloxacin to microbiological clearance cannot be determined. Full article

Pain is a complex process involving dynamic transcriptional changes in cells of the PNS and CNS following injury or inflammation. Among stress-inducible transcription factors, ATF3 has emerged as one of the most robust molecular markers of neuronal injury, particularly in sensory neurons of the DRG. Although ATF3 is widely used as an indicator of axonal damage in experimental pain models, its functional contribution to the initiation, maintenance, and resolution of pain remains poorly understood. Recent transcriptomic and functional studies suggest that ATF3 not only reflects neuronal stress but also orchestrates gene expression programs involved in axonal regeneration, neuroimmune communication, ion channel remodeling, and nociceptor plasticity. Moreover, ATF3 expression has been identified in non-neuronal cell populations, including Schwann cells and satellite glial cells, indicating broader roles in peripheral nerve repair and neuroinflammation. Despite the growing body of experimental evidence, the literature remains fragmented, and no consensus has yet been reached as to whether ATF3 primarily promotes adaptive regeneration or directly contributes to maladaptive pain signaling. This review aims to provide a comprehensive and critical overview of the current understanding of ATF3 biology in pain, building on evidence from transcriptomic and molecular analyses, experimental models of neuropathic, inflammatory, and cancer-associated pain, and emerging mechanistic insights into its role in pain-related neuronal plasticity. This review examines the regulation of ATF3 expression, its downstream transcriptional targets, its interactions with inflammatory signaling pathways, and its potential value as a therapeutic target. By consolidating current evidence and highlighting existing knowledge gaps, this review seeks to clarify the multifaceted role of ATF3 in pain pathophysiology. Full article

Sulfated polysaccharides from red seaweeds are emerging as versatile bioactive macromolecules. Here, we report that funoran-type galactans from Gelidiopsis variabilis (GV) function as immunometabolic reprogrammers, orchestrating inflammation resolution through targeted remodeling of amino acid and fatty acid metabolism in macrophages, potentially via receptor-mediated pathways. Cold and hot water extraction yielded structurally distinct fractions (360–3006 kDa) characterized by NMR as sulfated galactans with κ-carrageenan motifs and variable sulfation (6.6–21.5%). In RAW264.7 macrophages, fractions GV-1A and GV-2A induced an anti-inflammatory metabolic state characterized by arginine accumulation (from 4.61% to 7.06% of the total amino acid pool), reduced ornithine levels, and complete the elimination of pro-inflammatory myristate (14:0), while upregulating phagocytosis (149% of control). In a carrageenan-induced paw edema model, GV-1A and GV-2A dose-dependently upregulated pro-resolution markers (IL-10, IL-4, TGF-β1, Arg1, HO-1), outperforming the standard drug meloxicam. While the in vitro arginine accumulation suggests functional arginase inhibition, the in vivo Arg1 upregulation reflects a transcriptional response in a complex tissue environment. We propose that these findings collectively support a ‘resolution-phase metabolic phenotype’, a working model whereby GV polysaccharides reprogram macrophage metabolism toward inflammation resolution through context-dependent mechanisms. These findings establish G. variabilis polysaccharides as metabolically active immunomodulators that promote inflammation resolution, with the potential for applications in inflammatory diseases and as a pharmaceutical platform for drug development. Full article

Background: Sickle cell disease (SCD) is a systemic disorder marked by chronic pain and neurocognitive deficits, yet the molecular drivers of these neurocognitive features remain poorly defined. Platelets, central to inflammation and vascular homeostasis, may reflect broad pathophysiologic processes in SCD. Methods: We performed high-resolution mass spectrometry on ultra-purified platelets from 16 adults with SCD and moderate to severe pain (self-reported ≥ 3/10 in the past year), identifying 4196 proteins, of which 1046 were significant (FDR < 0.05). Unsupervised clustering was used to stratify individuals into high- and low-pain phenotypes. Results: Contrary to expectations, canonical pain pathways were not enriched. Instead, significant alterations were observed in neurodegeneration, mitochondrial metabolism, ATP regulation, mitophagy, and tRNA aminoacylation pathways between high- and low-pain phenotypes. High-pain individuals exhibited elevated levels of proteins involved in proteostasis and neurodegenerative disease processes, whereas low-pain individuals showed increased expression of proteins linked to mitochondrial integrity, neuroprotection, and reduced oxidative stress. Protein-protein interaction networks revealed tightly connected clusters within neurodegenerative and central nervous system-related pathways. Disease association analysis ranked neurodegenerative and mitochondrial pathways above traditional hematologic and nociceptive mechanisms. Conclusions: These findings suggest that platelet proteomics may serve as a peripheral window into PNS or CNS vulnerability and cognitive risk in SCD. The enrichment of tRNA aminoacylation and mitochondrial regulation pathways underscores the metabolic complexity of SCD and highlights novel targets for biomarker development and therapeutic intervention. Full article

Treat-to-target management in inflammatory bowel disease (IBD) combines symptoms, fecal and serum biomarkers, endoscopy, histology, and cross-sectional imaging, but these measures frequently diverge. Discordance may reflect analytical variation, timing, disease location, phenotype, comorbidity, or partially non-overlapping biological processes. We performed a critical narrative review using a structured PubMed/MEDLINE search, supplemented by citation chaining and publisher searches. Guidelines, systematic reviews, diagnostic studies, cohorts, randomized trials, and selected mechanistic studies were prioritized. Fecal calprotectin (FC) and lactoferrin primarily reflect intestinal neutrophilic inflammation, whereas C-reactive protein (CRP) and related serum indices reflect a nonlocalizing systemic response. The fecal immunochemical test (FIT) detects gastrointestinal bleeding, and leucine-rich alpha-2 glycoprotein (LRG) remains promising but insufficiently standardized. We distinguish five biological biomarker domains—namely, fecal–neutrophil; serum–systemic; epithelial/barrier; restitution/resolution; and fibrosis/extracellular matrix (ECM) remodeling—from symptoms and clinical indices, pharmacologic measurements, and phenotype-directed reference assessments. Circulating barrier, repair, and matrix-turnover markers remain investigational. Reactive therapeutic drug monitoring (TDM) for anti-tumor necrosis factor (anti-TNF) agents has the most mature evidence. Vedolizumab and ustekinumab show exposure–response associations, but actionable thresholds are unvalidated, and clinical TDM is not established for newer biologics or oral small molecules. After objective confirmation of disease activity, the framework may support phenotype-directed therapeutic decisions but is not a validated algorithm. Clinically important disagreement should prompt assessment of sampling, assay, timing, infection, medication-related confounding, and pretest probability before phenotype-directed endoscopy, histology, imaging, or reactive TDM is selected. A single discordant result should neither trigger treatment escalation nor exclude active or structural disease. Full article

Acute and chronic inflammation underlies the pathogenesis of numerous diseases, including autoimmune disorders, atherosclerosis, infections, and cancer. Although non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are widely used to control inflammation, their clinical utility is limited by adverse effects such as gastrointestinal toxicity and immunosuppression. Specialized pro-resolving mediators (SPMs), a family of endogenous lipid mediators derived from omega-3 fatty acids, have emerged as promising therapeutics because they actively promote the resolution of inflammation without suppressing host immunity. However, their clinical translation is hindered by poor chemical stability, rapid metabolic degradation, and short circulation half-lives. To overcome these limitations, a variety of delivery platforms—including liposomes, extracellular vesicles, PLGA nanoparticles, and hydrogels—have been developed to improve SPM stability, pharmacokinetics, and therapeutic efficacy. This review summarizes the cellular targets of SPMs, current delivery challenges, and emerging strategies for cell- and tissue-specific SPM delivery. We also discuss future opportunities for targeted SPM therapies in the treatment of inflammatory diseases and cancer. Full article

Regular exercise mediates inter-tissue communication between skeletal muscle and the immune system through skeletal muscle-derived secretory factors, providing an important molecular basis for the beneficial effects of exercise on chronic inflammation, metabolic dysregulation, and impaired tissue repair. As key effector cells of the innate immune system, macrophages do not simply conform to a dichotomous classification of classically activated M1 macrophages and alternatively activated M2 macrophages; rather, their functional states constitute a dynamic spectrum shaped by exercise load, recovery time window, tissue microenvironment, and disease context. This review focuses on recent advances in exercise-induced skeletal muscle secretory factors involved in macrophage functional remodeling. Representative signals, including interleukin-6 (IL-6), irisin, meteorin-like protein (METRNL), fibroblast growth factor 21 (FGF21), oncostatin M (OSM), decorin, myostatin, chemokines, and extracellular vesicles, are systematically summarized in terms of their exercise responsiveness, evidence for skeletal muscle origin, and evidence supporting macrophage regulation. Based on these dimensions, an evidence-strength grading framework is further proposed. Moreover, this review integrates key signaling axes, including glycoprotein 130 (gp130)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT), signal transducer and activator of transcription 6 (STAT6)/peroxisome proliferator-activated receptor gamma (PPARγ), AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (Nrf2)/nuclear factor kappa B (NF-κB), transforming growth factor beta (TGF-β)/Smad, and chemokine receptor pathways, to explain how exercise-induced secretory networks participate in the dynamic regulation of the macrophage functional spectrum through immune cell recruitment, inflammatory clearance, immunometabolic reprogramming, matrix remodeling, and repair-niche formation. Current evidence indicates the translational potential of exercise-induced skeletal muscle secretory factors in skeletal muscle repair, metabolic inflammation, aging-related functional decline, and cancer rehabilitation. However, this field still faces several major challenges, including insufficient tracing of skeletal muscle-derived signals, limited direct causal validation, a lack of human tissue-level evidence, and unclear exercise dose–response relationships. Future studies should combine tissue-specific genetic interventions, receptor blockade, single-cell and spatial omics, metabolic flux analysis, and standardized human exercise interventions to further clarify the mechanistic basis and application boundaries of exercise-induced skeletal muscle–macrophage communication, thereby providing a theoretical foundation for precision exercise prescription and chronic inflammation intervention. Full article