Skeletal Muscle Interleukin-6 Contributes to the Innate Immune Response in Septic Mice
Orlando Laitano, Gerard P. Robinson, Christian K. Garcia, Alex J. Mattingly, Laila Sheikh, Kevin Murray, John Iwaniec, Jamal M. Alzahrani, Deborah Morse, Juan Hidalgo, Thomas L. Clanton
Abstract
ABSTRACT: Interleukin-6 (IL-6) is a major cytokine released by skeletal muscle. Although IL-6 plays complex but well-known 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., TNFα 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.