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Interleukin-6/Signal Transducer and Activator of Transcription 3 (STAT3) Pathway Is Essential for Macrophage Infiltration and Myoblast Proliferation during Muscle Regeneration
Open accessAbstract
Inflammation and microenvironment play a crucial role in muscle regeneration. IL (interleukin)-6, as a multifunctional cytokine is involved in the processes. However, the causative effect of IL-6 in muscle regeneration remains unclear. In a mouse model of cardiotoxin-induced muscle injury/regeneration, infiltrated monocytes/macrophages produce a high level of IL-6 started on 1 day (24 h) after injury. In IL-6 knock-out (−/−) mice, the muscle regeneration procedure was impaired along with decreased myogenic determination factor (MyoD) and myogenin mRNA level and increased interstitial fibrosis. The IL-6 −/− mice exhibited less macrophage infiltration, lower inflammatory cytokine (IL-1β, inducible NO synthase, Transforming growth factor (TGF)-β1, and IL-10) and chemokine (CCL2, CCL3, and CCL5) expression, and inhibited myoblast proliferation. In vitro , IL-6 deficiency or Signal Transducer and Activator of Transcription 3 (STAT3) knockdown in activated macrophage attenuated the expression of CCL2, CCL3, but not CCL5, which resulted in less macrophage migration. Moreover, inflammatory macrophages promoted myoblast proliferation in an IL-6-dependent manner. Finally, adoptive transfer IL-6 +/+ BM cells into IL-6 −/− mice rescued the impaired regeneration with improved MyoD and myogenin expression. Taken together, IL-6 expression and the activated STAT3 signaling pathway in monocytes/macrophages is a critical mediator of macrophage migration and myoblast proliferation during muscle regeneration. Background: Interleukin-6 (IL-6), as a multifunctional cytokine, was involved in the inflammation microenvironment of muscle regeneration. Results: In mice lacking IL-6, less macrophage recruitment and decreased myoblast proliferation impairs muscle regeneration. Conclusion: In monocytes/macrophages, activation of the IL-6/STAT3 pathway is critical to macrophage migration and myoblast proliferation during muscle regeneration. Significance: IL-6/STAT3 pathway is essential for muscle regeneration.
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“Acute transient increases in inflammation plays an important part in the early regenerative processes of muscle adaptation, particularly in response to exercise [54,55].”
From Potential Roles of n-3 PUFAs during Skeletal Muscle Growth and Regeneration (2018) · cites this paper as [55]
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Diet‐induced obesity alters anabolic signalling in mice at the onset of skeletal muscle regeneration
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“IL-6 plays a role in the recruitment and infiltration of phagocytes to the injured site of muscle at the onset of skeletal muscle regeneration (Zhang et al. 2013).”
BackgroundResultInfluentialMadaro, L., & Bouché, M. (2014) · BioMed Research International · doi:10.1155/2014/438675 · Cited by 66
“Much of the current information about the role of immune cell populations of the innate response in muscle repair comes from studies on healthy regenerating muscle [1, 18–20].”
BackgroundCX 3 CR1 deficiency delays acute skeletal muscle injury repair by impairing macrophage functions
Zhao, W., Lu, H., Wang, X., Ransohoff, R. M., & Zhou, L. (2015) · The FASEB Journal · doi:10.1096/fj.14-270090 · Cited by 70
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“(36) showing that IL-6 is critical in promoting macrophage infiltration in the muscle regeneration process, as well as the suggestion by Pei et al.”
BackgroundRole of interleukin-6 in regulation of immune responses to remodeling after myocardial infarction
Huang, M., Du, Y., Xiang, M., & Wang, J. (2014) · Heart Failure Reviews · doi:10.1007/s10741-014-9431-1 · Cited by 67
“IL-6 expression and the activated STAT3 signaling pathway in monocytes/macrophages is a critical mediator of macrophage migration and myoblast proliferation during muscle regeneration [78].”
BackgroundSarma, N. J., Tiriveedhi, V., Crippin, J. S., Chapman, W. C., & Mohanakumar, T. (2014) · Journal of Virology · doi:10.1128/jvi.03060-13 · Cited by 63
“Components of the IL-6R complex were shown to be essential for CCL2 expression (10).”
BackgroundRole of inflammasomes and cytokines in immune dysfunction of liver cirrhosis
Das, P. P., & Medhi, S. (2023) · Cytokine · doi:10.1016/j.cyto.2023.156347 · Cited by 65
MicroRNA-223-3p promotes skeletal muscle regeneration by regulating inflammation in mice
Cheng, N., Liu, C., Li, Y., Gao, S., Han, Y., Wang, X., Du, J., & Zhang, C. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.012263 · Cited by 62
“After acute muscle injury, the infiltrated macrophage is the main cellular source, and the increased IL-6 could stimulate the proliferation of MuSCs and promote the expression of chemokines CCL2 and CCL3 inmacrophages, which further enhances the infiltration of macrophages (8).”
BackgroundMethodResultInfluentialNrf2 augments skeletal muscle regeneration after ischaemia–reperfusion injury
Al‐Sawaf, O., Fragoulis, A., Rosen, C., Keimes, N., Liehn, E. A., Hölzle, F., Kan, Y. W., Pufe, T., Sönmez, T. T., & Wruck, C. J. (2014) · The Journal of Pathology · doi:10.1002/path.4418 · Cited by 59
“Recently, Zhang et al showed that interleukin-6 (IL-6) produced in macrophages is critical for MyoD activation and myoblast proliferation during muscle regeneration [21].”
BackgroundTuning Macrophage Phenotype to Mitigate Skeletal Muscle Fibrosis
Stepien, D. M., Hwang, C. D., Marini, S., Pagani, C. A., Sorkin, M., Visser, N. D., Huber, A. K., Edwards, N., Loder, S. J., Vasquez, K., et al. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1900814 · Cited by 62
“Deletion of the proinflammatory cytokine IL-6 prevents macrophage recruitment to the site of injury with impairment of muscle regeneration (19).”
BackgroundKato, H., Miura, K., Nakano, S., Suzuki, K., Bannai, M., & Inoue, Y. (2016) · Amino Acids · doi:10.1007/s00726-016-2240-1 · Cited by 57
“However, IL-6 is also essential for muscle regeneration (Zhang et al. 2013), because, it regulates myoblast proliferation and differentiation (Serrano et al. 2008).”
BackgroundAge-associated inflammation and implications for skeletal muscle responses to exercise
Kunz, H. E., & Lanza, I. R. (2023) · Experimental Gerontology · doi:10.1016/j.exger.2023.112177 · Cited by 56
“This inflammatory environment appears crucial for recovery, as pre-clinical studies show that skeletal muscle regenerative capacity is impaired in the absence of TNFα, IL6, or IFN-γ (Peake et al., 2017; Serrano et al., 2008; Zhang et al., 2013; Collins and Grounds, 2001).”
BackgroundBeiter, T., Hoene, M., Prenzler, F., Mooren, F. C., Steinacker, J. M., Weigert, C., Niess, A. M., & Munz, B. (2026) · PubMed · doi:10.22029/eir.2015.1695 · Cited by 56
Wang, X., Zhao, W., Ransohoff, R. M., & Zhou, L. (2018) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2018.01.004 · Cited by 58
“IL-6 is not only a pro-inflammatory cytokine but also an important regulator of satellite cell proliferation during muscle injury repair (Serrano et al., 2008; Begue et al., 2013; Zhang et al., 2013).”
The Importance of Biophysical and Biochemical Stimuli in Dynamic Skeletal Muscle Models
Maleiner, B., Tomasch, J., Heher, P., Oliver Spadiut, A., Rünzler, D., & Fuchs, C. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.01130 · Cited by 60
“Studies in rodents demonstrated that production of IL-6 and leukemia inhibitory factor help to regenerate muscle tissue after injury by activating satellite cells (Barnard et al., 1994; Kurek et al., 1996, 1997; Zhang et al., 2013).”
BackgroundGorski, T., Mathes, S., & Krützfeldt, J. (2018) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12277 · Cited by 56
“display smaller myofibers than wild-type mice 15 days after CTX-induced muscle injury.(62) Furthermore, increases in”
BackgroundMechanisms of cooperative cell-cell interactions in skeletal muscle regeneration
Koike, H., Manabe, I., & Oishi, Y. (2022) · Inflammation and Regeneration · doi:10.1186/s41232-022-00234-6 · Cited by 58
“Indeed, systemic deletion of Il-6 was shown to prevent macrophage recruitment to the site of injury, and muscle regeneration was impaired, with decreased MYOD and myogenin expression in myoblasts [52].”
BackgroundRingleb, M., Javelle, F., Haunhorst, S., Bloch, W., Fennen, L., Baumgart, S., Drube, S., Reuken, P. A., Pletz, M. W., Wagner, H., et al. (2024) · The FASEB Journal · doi:10.1096/fj.202301619r · Cited by 73
“In the regenerating muscle, IL-6 is released by infiltrating neutrophils and macrophages, 112 by fibro-adipogenic progenitors, 113 and by satellite cells, 114,115 suggesting possible autocrine and paracrine functions of IL-6 in satellite cell-dependent myogenesis.”
BackgroundGitiaux, C., Latroche, C., Weiss‐Gayet, M., Rodero, M. P., Duffy, D., Bader‐Meunier, B., Glorion, C., Nusbaum, P., Bodemer, C., Mouchiroud, G., et al. (2017) · Arthritis & Rheumatology · doi:10.1002/art.40328 · Cited by 57
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“They remove muscle debris resulting from trauma and secrete cytokines, such as tumor necrosis factor α (TNF-α ) and Interleukin 6 (IL-6), which amplify the inflammatory status [58,59].”
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HDAC4 promotes Pax7‐dependent satellite cell activation and muscle regeneration
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Freire, P. P., Fernández, G. J., Cury, S. S., de Moraes, D., Oliveira, J. S., de Oliveira, G., Dal‐Pai‐Silva, M., Reis, P. P., & Carvalho, R. F. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20081962 · Cited by 45
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Deficiency of IL-12p35 improves cardiac repair after myocardial infarction by promoting angiogenesis
Kan, X., Wu, Y., Ma, Y., Zhang, C., Li, P., Wu, L., Zhang, S., Li, Y., & Du, J. (2015) · Cardiovascular Research · doi:10.1093/cvr/cvv255 · Cited by 46
Immunometabolism of macrophages regulates skeletal muscle regeneration
Chen, Y.-F., Lee, C., Wu, H.-H., Lin, W., & Lee, O. K. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.948819 · Cited by 46
“In IL-6 deficient mice, the proliferation of MuSCs was abrogated (Serrano et al., 2008; Zhang et al., 2013), and IL-6 is also necessary for the complete differentiation of muscle cells.”
BackgroundAlves, A. N., Ribeiro, B., Fernandes, K., Souza, N., Rocha, L. A., Nunes, F., Bussadori, S., & Mesquita-Ferrari, R. (2016) · Lasers in Medical Science · doi:10.1007/s10103-016-1908-9 · Cited by 36
“[26] found that monocytes/macrophages expressed the highest level of IL-6 mRNA, whereas muscle-resident cells (including myoblasts and fibroblasts) expressed very low levels.”
BackgroundThe multifaceted role of macrophages in homeostatic and injured skeletal muscle
Wang, X., & Zhou, L. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1274816 · Cited by 45
Regulatory role of microRNAs in virus-mediated inflammation
Baghi, H. B., Bayat, M., Mehrasa, P., Alavi, S. M. A., Lotfalizadeh, M. H., Memar, M. Y., Taghavi, S. P., Zarepour, F., Hamblin, M. R., Nahand, J. S., et al. (2024) · Journal of Inflammation · doi:10.1186/s12950-024-00417-7 · Cited by 43
“It has been demonstrated that reduction of IL-6 and IL-6R complex, along with STAT3 in mice results in downregulation of CCL2 [142].”
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“However, studies have shown that IL-6 is a hepatoprotective factor, which can predict alcoholic liver injury [46,47].”
BackgroundXiao, S., Huang, G., Wei, Z., Nie, K., Liu, Z., Deng, C., & Wang, D. (2019) · Stem Cells International · doi:10.1155/2019/9158016 · Cited by 40
“IL-6 is a proinflammatory cytokine that exerts multiple effects in direct opposition to the anti-inflammatory cytokine IL-10, such as increasing inflammatory cell infiltration [22].”
BackgroundMicroRNA-570-3p regulates HuR and cytokine expression in airway epithelial cells.
Roff, A. N., Craig, T., August, A., Stellato, C., & Ishmael, F. T. (2014) · Europe PMC (PubMed Central) · Cited by 38
Gnanaprakasam, J. N. R., Estrada-Muñiz, E., & Vega, L. (2015) · International Immunopharmacology · doi:10.1016/j.intimp.2015.08.038 · Cited by 37
Glycerol-induced injury as a new model of muscle regeneration
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MicroRNA regulated macrophage activation in obesity
Li, C., Qu, L., Farragher, C., Vella, A. T., & Zhou, B. (2019) · Journal of Translational Internal Medicine · doi:10.2478/jtim-2019-0011 · Cited by 38
“[17] Interestingly, both M1 and M2 macrophages produce cytokine IL-6 that has both proinflammatory and anti-inflammatory functions[18] and is known to promote insulin secretion[19] or skeletal muscle tissue repair, depending on specific conditions.[20] M1 macrophages also release reactive molecules such as nitric oxid…”
Background
Metadata
- Authors
- Zhang, C., Li, Y., Wu, Y., Wang, L., Wang, X., & Du, J.
- Affiliations
- Capital Medical University (CN)
- Corresponding author
- Du, Jie
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 288
- Issue
- 3
- Pages
- 1489-1499
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3548462
- OpenAlex
- W1969630360
- Cited by
- 279
- References
- 37
- Citations by year
- 2026: 16 · 2025: 15 · 2024: 21 · 2023: 17 · 2022: 20 · 2021: 23 · 2020: 21 · 2019: 20 · 2018: 27 · 2017: 25 · 2016: 22 · 2015: 19 · 2014: 20 · 2013: 12
- FWCI
- 6.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR060268)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- interleukin-6, STAT3 signaling, muscle regeneration, macrophage infiltration, myoblast proliferation, cardiotoxin-induced muscle injury, IL-6 knockout mice, macrophage migration, MyoD, myogenin, interstitial fibrosis, inflammatory cytokines, bone marrow-derived macrophages
- MeSH terms
- Animals, Cell Movement, Gene Expression Regulation, Macrophages, Regeneration, RNA, Messenger, Signal Transduction, Interleukin-6, MyoD Protein, Myogenin, Mice, Knockout, Muscle, Skeletal, Myoblasts, Cell Proliferation, STAT3 Transcription Factor, Mice, Cardiotoxins, Primary Cell Culture
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