Skeletal Muscle Myofibers Directly Contribute to LPS-Induced Systemic Inflammatory Tone
The abundance, anatomical distribution, and vascularity of skeletal muscle make it a potentially important contributor to local cytokine production and systemic cytokine abundance during inflammatory events. An orchestrated balance between the production of pro- and anti-inflammatory mediators is ne...
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| Format: | Article |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.917917/full |
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| author | Joseph J. Bivona III Madeleine M. Mank Renee D. Stapleton D. Clark Files Michael J. Toth Matthew E. Poynter |
| author_facet | Joseph J. Bivona III Madeleine M. Mank Renee D. Stapleton D. Clark Files Michael J. Toth Matthew E. Poynter |
| author_sort | Joseph J. Bivona III |
| collection | DOAJ |
| description | The abundance, anatomical distribution, and vascularity of skeletal muscle make it a potentially important contributor to local cytokine production and systemic cytokine abundance during inflammatory events. An orchestrated balance between the production of pro- and anti-inflammatory mediators is necessary for proper immune function, yet the contribution of the body’s largest organ system, comprised primarily of skeletal muscle myocytes that fuse to form myofibers, to this process is largely unknown. Endotoxin (lipopolysaccharide, LPS) stimulates toll-like receptor 4 (TLR4) to induce the production of several pro-inflammatory cytokines, including interleukin-6 (IL-6) and C-C motif chemokine ligand 2 (CCL2), by a of myriad cell types. We sought to quantify the influence of myofibers on systemic cytokine concentrations following an acute endotoxemia challenge. To accomplish this, we generated muscle specific conditional knockouts for TLR4 (TLR4SMKO), IL-6 (IL6SMKO), and CCL2 (CCL2SMKO). We administered low concentrations of intravenous LPS (IV LPS) to these receptor and effector knockout mice and collected samples after 3 h. Using gene expression analysis of gastrocnemius muscle and serum cytokine measurements after IV LPS, we determined that deletion of myofiber IL-6 or CCL2 led to a 93% and 57% reduction of these specific cytokines in the systemic circulation, respectively. Myofiber specific TLR4 deletion decreased the expression of IL-6, CCL2, and C-X-C motif chemokine ligand 1 (CXCL1) in the gastrocnemius muscle. These data indicate the critical involvement and direct contribution of myofibers during the early systemic inflammatory cytokine response to endotoxin. |
| first_indexed | 2024-04-13T17:20:53Z |
| format | Article |
| id | doaj.art-e7200224a5e04872808de9dd9aa86fda |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T17:20:53Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-e7200224a5e04872808de9dd9aa86fda2022-12-22T02:38:00ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-06-011310.3389/fphar.2022.917917917917Skeletal Muscle Myofibers Directly Contribute to LPS-Induced Systemic Inflammatory ToneJoseph J. Bivona III0Madeleine M. Mank1Renee D. Stapleton2D. Clark Files3Michael J. Toth4Matthew E. Poynter5Department of Medicine and Vermont Lung Center, University of Vermont Larner College of Medicine, Burlington, VT, United StatesDepartment of Medicine and Vermont Lung Center, University of Vermont Larner College of Medicine, Burlington, VT, United StatesDepartment of Medicine and Vermont Lung Center, University of Vermont Larner College of Medicine, Burlington, VT, United StatesDepartment of Internal Medicine, Section on Pulmonary, Critical Care, Allergy and Immunology, Wake Forest School of Medicine, Winston-Salem, NC, United StatesDepartment of Medicine and Vermont Lung Center, University of Vermont Larner College of Medicine, Burlington, VT, United StatesDepartment of Medicine and Vermont Lung Center, University of Vermont Larner College of Medicine, Burlington, VT, United StatesThe abundance, anatomical distribution, and vascularity of skeletal muscle make it a potentially important contributor to local cytokine production and systemic cytokine abundance during inflammatory events. An orchestrated balance between the production of pro- and anti-inflammatory mediators is necessary for proper immune function, yet the contribution of the body’s largest organ system, comprised primarily of skeletal muscle myocytes that fuse to form myofibers, to this process is largely unknown. Endotoxin (lipopolysaccharide, LPS) stimulates toll-like receptor 4 (TLR4) to induce the production of several pro-inflammatory cytokines, including interleukin-6 (IL-6) and C-C motif chemokine ligand 2 (CCL2), by a of myriad cell types. We sought to quantify the influence of myofibers on systemic cytokine concentrations following an acute endotoxemia challenge. To accomplish this, we generated muscle specific conditional knockouts for TLR4 (TLR4SMKO), IL-6 (IL6SMKO), and CCL2 (CCL2SMKO). We administered low concentrations of intravenous LPS (IV LPS) to these receptor and effector knockout mice and collected samples after 3 h. Using gene expression analysis of gastrocnemius muscle and serum cytokine measurements after IV LPS, we determined that deletion of myofiber IL-6 or CCL2 led to a 93% and 57% reduction of these specific cytokines in the systemic circulation, respectively. Myofiber specific TLR4 deletion decreased the expression of IL-6, CCL2, and C-X-C motif chemokine ligand 1 (CXCL1) in the gastrocnemius muscle. These data indicate the critical involvement and direct contribution of myofibers during the early systemic inflammatory cytokine response to endotoxin.https://www.frontiersin.org/articles/10.3389/fphar.2022.917917/fullskeletal musclecytokineendotoxinTLR4–toll-like receptor 4LPS (lipopolysaccharide)inflammation |
| spellingShingle | Joseph J. Bivona III Madeleine M. Mank Renee D. Stapleton D. Clark Files Michael J. Toth Matthew E. Poynter Skeletal Muscle Myofibers Directly Contribute to LPS-Induced Systemic Inflammatory Tone Frontiers in Pharmacology skeletal muscle cytokine endotoxin TLR4–toll-like receptor 4 LPS (lipopolysaccharide) inflammation |
| title | Skeletal Muscle Myofibers Directly Contribute to LPS-Induced Systemic Inflammatory Tone |
| title_full | Skeletal Muscle Myofibers Directly Contribute to LPS-Induced Systemic Inflammatory Tone |
| title_fullStr | Skeletal Muscle Myofibers Directly Contribute to LPS-Induced Systemic Inflammatory Tone |
| title_full_unstemmed | Skeletal Muscle Myofibers Directly Contribute to LPS-Induced Systemic Inflammatory Tone |
| title_short | Skeletal Muscle Myofibers Directly Contribute to LPS-Induced Systemic Inflammatory Tone |
| title_sort | skeletal muscle myofibers directly contribute to lps induced systemic inflammatory tone |
| topic | skeletal muscle cytokine endotoxin TLR4–toll-like receptor 4 LPS (lipopolysaccharide) inflammation |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.917917/full |
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