Skeletal Muscle Interleukin-6 Contributes to the Innate Immune Response in Septic Mice

Abstract

) is a major cytokine released by skeletal muscle. Although IL-6 plays complex but wellknown roles in host defense, the specific contribution of skeletal muscle IL-6 to innate immunity remains unknown. We tested its functional relevance by exposing inducible skeletal muscle IL-6 knockdown (skmIL-6KD) mice to a cecal slurry model of polymicrobial peritonitis and compared responses to strain-matched controls and skeletal muscle Cre-matched controls at 3, 6, and 12 h postinfection. In both sexes, skmIL-6KD mice at 6 h of infection exhibited marked changes to leukocyte trafficking in the peritoneum, characterized by $1.75-fold elevation in %neutrophils, a $3-fold reduction in %lymphocytes and a $2 to 3-fold reduction in %basophils. A similar pattern was seen at 12 h. No changes were observed in plasma leukocyte counts. Circulating cytokines in female skmIL-6KD mice at 6 h consistently showed modest reductions in IL-6, but marked reductions in a broad range of both pro-and anti-inflammatory cytokines, e.g., TNFa and IL-10. In both sexes at 12 h, a generalized suppression of plasma cytokines was also seen after the effects of Cre-induction with raloxifene were addressed. There were no significant effects of skmIL-6KD on mortality in either sex. Collectively, our results are consistent with skmIL-6 playing an important and previously unrecognized role in immune cell trafficking and cytokine regulation during septic shock.

Macrophages augment the skeletal muscle proinflammatory response through TNFα following LPS‐induced acute lung injury

“…While protein translation is variable, we predict muscle is actively secreting cytokines into circulation, leading to limited detection within muscle. Although skeletal muscle may not be the primary source of circulating IL-6 following IT-LPS, it has been recently demonstrated using a skeletal muscle-specific Il6 knockdown mouse 27 that skeletal muscle-derived IL-6 contributes to systemic IL-6 levels and the concentrations of TNFα and IL-10 in a model of polymicrobial sepsis. The contribution of other skeletal F I G U R E 5 TNFα is sufficient for synergistic increase in cytokine expression in vitro, but not in vivo.…”

The impact of hindlimb disuse on sepsis‐induced myopathy in mice

“…Besides locomotive reasons, which include the ability to live a functional life, there are several ways in which skeletal muscles participate in immune function in response to sepsis and other stress‐induced illnesses. For example, skeletal muscles serve as a cytokine response organ during muscle contraction and exposure to pathogen‐ or damage‐associated molecular patterns (PAMPS and DAMPS) or in response to cellular stress (Laitano, Robinson, Garcia, et al, 2021; Laitano, Robinson, Murray, et al, 2021; Lang et al, 2003; Welc et al, 2016). Skeletal muscles can also serve as a source of acute phase proteins (APPs) (Iwaniec et al, 2021; Langhans et al, 2014) and amino acid substrates to support highly metabolic tissues such as liver, kidney, and bone marrow (Karinch et al, 2001), and as part of a complex network of resident immunosensitive cells that reside together within muscle bundles (Côt́e et al, 2008; Howard et al, 2020; McLennan, 1993).…”

“…Data from prospective clinical studies indicate that 54% of septic patients admitted to ICU over the course of a year were males and 46% were female (Nasir et al, 2015). We only studied male mice in the present study and it is well known that there are different responses between male and female mice regarding the skeletal muscle response in the context of sepsis (Laitano, Robinson, Garcia, et al, 2021; Laitano, Robinson, Murray, et al, 2021). In addition, we did not monitor food intake in the present study.…”

The Role of Skeletal Muscles in Exertional Heat Stroke Pathophysiology

“…Note that, in general, these stimuli are thought to be part of EHS pathophysiology. Thus, skeletal muscle can be seen as an organ able to sense signals arising from other physiological systems, including immunological cells and bacterial sources via toll-like receptors [15]. Toll-like receptors are a class of proteins that plays a crucial role in immune system signaling by recognizing pathogenassociated molecular patterns from various microbes [63].…”