While mammals tend to repair injuries, other adult vertebrates like salamanders and fish regenerate damaged tissue. One prominent hypothesis offered to explain an inability to regenerate complex tissue in mammals is a bias during healing toward strong adaptive immunity and inflammatory responses. Here we directly test this hypothesis by characterizing part of the immune response during regeneration in spiny mice (Acomys cahirinus and Acomys percivali) vs. fibrotic repair in Mus musculus. By directly quantifying cytokines during tissue healing, we found that fibrotic repair was associated with a greater release of pro-inflammatory cytokines (i.e., IL-6, CCL2, and CXCL1) during acute inflammation in the wound microenvironment. However, reducing inflammation via COX-2 inhibition was not sufficient to reduce fibrosis or induce a regenerative response, suggesting that inflammatory strength does not control how an injury heals. Although regeneration was associated with lower concentrations of many inflammatory markers, we measured a comparatively larger influx of T cells into regenerating ear tissue and detected a local increase in the T cell associated cytokines IL-12 and IL-17 during the proliferative phase of regeneration. Taken together, our data demonstrate that a strong adaptive immune response is not antagonistic to regeneration and that other mechanisms likely explain the distribution of regenerative ability in vertebrates.

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.