Interleukin-1 signaling contributes to endurance training-induced skeletal muscle adaptations.

Effects of Electrical Muscle Stimulation on Skeletal Muscle During Lipopolysaccharide-Induced Inflammation: A Controlled Murine Study.

EMS applied during LPS-induced systemic inflammation exacerbated skeletal muscle atrophy and was associated with activation of IL-6/STAT3-C/EBPδ signaling and proteolytic pathways.

Interleukin-33 at the intersection of inflammation and repair

Interleukin 33 (IL-33) is a cytokine of the IL-1 family that acts as an alarmin in both innate and adaptive immunity. IL-33 is constitutively nuclear in epithelial and endothelial cells, where its activity is limited by nuclear retention. Release of IL-33 in response to cellular stress or injury can mediate type 2 immune responses or tissue repair, depending on the local tissue environment. IL-33 activity is regulated at multiple levels, including nuclear retention, oxidation, proteolytic processing, and metabolic regulation. Following its release, oxidation rapidly suppresses IL-33 activity, while mast cell and neutrophil proteases can generate smaller active fragments that target cells expressing the IL-33 ST2 receptor. Simultaneously, tissue metabolic status influences cellular responsiveness through the mTORC1 and AMPK pathways, which link metabolic capacity to effector function. These conditions may explain why IL-33 can mediate an inflammatory response, but in other circumstances, it contributes to tissue repair. Such pleiotropic properties may also underline the variability in clinical responses to IL-33/ST2-targeted therapies across various diseases. The appreciation of IL-33 as a cytokine whose activity is conditioned by its structural, redox, and metabolic environment is critical to optimizing its therapeutic potential as a target.

IL-1β-Induced Inflammatory Transcriptome and TGF-β1 Attenuation of Chemokine Expression in ACL Remnant Fibroblasts.

BACKGROUND The high incidence of posttraumatic osteoarthritis after anterior cruciate ligament (ACL) injury and reconstruction suggests that biological mechanisms beyond joint instability contribute to disease progression. After injury, ACL-resident cells are exposed to inflammatory mediators within the joint and may influence the local inflammatory microenvironment; however, their global transcriptomic responses to inflammatory stimuli remain underexplored. HYPOTHESIS Interleukin-1 beta (IL-1β) induces inflammatory transcriptomic responses in ACL remnant-derived (ACLr) fibroblasts, and transforming growth factor beta 1 (TGF-β1) attenuates these responses. STUDY DESIGN Descriptive laboratory study. METHODS Primary ACLr fibroblasts were isolated from ACL remnants (n = 10) collected at the time of knee surgery. Near-confluent cultures were treated with IL-1β (10 ng/mL) for 24 hours to model an inflammatory joint environment. Genome-wide transcriptional changes were assessed by RNA sequencing using an Illumina NovaSeq-6000, with selected targets confirmed by microfluidic digital polymerase chain reaction (PCR). To evaluate the effects of TGF-β1, ACLr fibroblasts pretreated with IL-1β were exposed to TGF-β1 (10 ng/mL) for 48 hours, and chemokine transcript levels were assessed using digital PCR. RESULTS IL-1β induced broad inflammatory transcriptional responses characterized by upregulation of chemokines (CXCL6, CXCL8, CXCL5, CCL20, CXCL1, and CXCL3), cytokines (IL33, IL1B, and IL6), and matrix-degrading enzymes (MMP3 and MMP12), while suppressing extracellular matrix-associated genes (KRT14, COL21A1, POSTN, COL1A1, and COL6A3). Functional enrichment analysis demonstrated activation of immune and inflammatory responses, cytokine and chemokine signaling, and cell activation. TGF-β1 reduced the expression of all assessed IL-1β-induced chemokines, with reduction of up to 50%, with statistically significant suppression observed for 13 of the 16 chemokines. Concomitantly, TGF-β1 treatment reduced expression of CEBPB, NFKBIA, and NFKBIZ, transcripts implicated in inflammatory gene regulation. CONCLUSION ACLr fibroblasts mounted a robust inflammatory transcriptomic response to IL-1β, characterized by marked induction of chemokines and inflammatory pathways. TGF-β1 attenuated many of these responses, supporting its role as a regulator of inflammatory signaling in ACL-resident cells. CLINICAL RELEVANCE ACL-resident cells respond to injury and may contribute to the post-injury inflammatory microenvironment. Therapeutic modulation of inflammatory signaling in these cells could represent a strategy to mitigate early molecular events associated with post-traumatic osteoarthritis following ACL tear.

IL27 exerts a powerful effect on systolic overload-induced cardiac inflammation, fibrosis, and heart failure development

Exercise-Induced Skeletal Muscle Secretory Factors and Macrophage Functional Remodeling: Mechanistic Advances

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.

Autophagic responses to vigorous endurance exercise in men vary by training status but are similar in PBMCs and skeletal muscle: A pilot study

Vigorous exercise triggers signaling cascades that activate autophagy markers like the degradation of sequestosome 1 (p62) and accumulation of Light Chain 3 II (LC3II). Limited human data exist on autophagic responses across different local and systemic tissues and how training status affects these relationships. This study investigates the vigorous exercise‐induced changes in p62 and LC3II expression in peripheral blood mononuclear cells (PBMCs) and skeletal muscle between endurance‐trained and untrained men. Twelve men (endurance‐trained n = 7, untrained n = 5) completed 60 min of cycling at their second ventilatory threshold. Skeletal muscle biopsy samples and PBMCs were collected pre‐ and 3‐h post‐exercise and analyzed for p62 and LC3II protein expression. We found significant interaction effects of time and training status for p62 (p < 0.001) and LC3II (p = 0.002). In untrained men, p62 decreased in PBMCs (FC = 0.50 ± 0.14; p < 0.001) and skeletal muscle (FC = 0.57 ± 0.21; p < 0.001), while LC3II increased in both tissues (FC = 1.74 ± 0.79; p = 0.019 for PBMCs; FC = 1.69 ± 0.47; p = 0.033 for skeletal muscle). No changes were observed in endurance‐trained men (all p > 0.05). These results suggest that a bout of vigorous endurance exercise increased autophagy‐related markers in both skeletal muscle and PBMCs in the untrained men only, suggesting a diminished autophagic response in the trained men.