Abstract
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.
Highlights
In response to damage, vertebrate tissue regeneration occurs as a chronological and overlapping series of processes that includes hemostasis, inflammation, re-epithelialization, activation of local progenitor cells, tissue morphogenesis, and replacement of the injured tissue
KC)) using a custom-designed sandwich ELISA array. We used this assay to compare five groups: three at the University of Kentucky, [1] laboratory-reared, outbred Mus musculus (MmUKY), [2] wild-caught M. musculus (Mm-Wild), [3] laboratoryreared Acomys cahirinus (Ac), and two at the University of Nairobi, [4] outbred M. musculus reared by a local breeder (MmKenya) and [5] wild-caught A. percivali (Ap) (Figure 1A)
Several cytokines not present in Acomys serum were quantified in tissue lysate (Ac: IL-1β, IL-4, IL-6, IL-17, CSF2, CCL2; Acomys percivali (Ap): IL-17, CSF2, CXCL1) supporting that the serum concentration was below the limit of detection and that the antibody binding epitopes were conserved between species
Summary
Vertebrate tissue regeneration occurs as a chronological and overlapping series of processes that includes hemostasis, inflammation, re-epithelialization, activation of local progenitor cells, tissue morphogenesis, and replacement of the injured tissue. Tissue Regeneration and Adaptive Immunity subsequently re-enter the cell cycle and self-organize to undergo morphogenesis [3, 4]. This transition from an inflammatory environment to morphogenesis is synonymous with formation of a regenerative blastema [5]. The injured tissue must precisely coordinate dynamic interactions between cells and factors (i.e., cytokines, chemokines, growth factors etc.) within the injury microenvironment to resolve the inflammatory response and promote blastema formation
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