Mammalian musculoskeletal regeneration is associated with reduced inflammatory cytokines and an influx of T cells.

Abstract

Whether the immune response to injury contributes to tissue regeneration is not well understood. We quantified systemic and local cytokines during ear pinna repair to provide the first comprehensive comparison of the immune response to injury between mammalian regeneration (A. cahirinus and A. percivali) and fibrotic repair (M. musculus). Importantly, by comparing laboratory-reared and wild-caught animals we identified responses specifically associated with healing outcome. Fibrotic repair showed a greater local release of IL-6, CCL2 and CXCL1. Conversely, regeneration showed decreased circulating IL-5, IL-6, IL-17, CCL3 and CXCL1 and increased local IL-12 and IL-17. The differential IL-6 response was substantiated by increased pSTAT3 during the inflammatory phase of fibrotic repair and with blastema formation and tissue morphogenesis in Acomys. COX-2 inhibition was not sufficient to induce regeneration. Interestingly, a unique influx of lymphocytes was coupled with regeneration and RNA-expression analysis suggested they were regulatory T cells. Together, the data support regeneration-specific inflammation and T cell responses in Acomys.