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.
Digital Object Identifier (DOI)
This work was provided by the National Science Foundation (NSF) and the Office for International Science and Engineering (OISE) to AS (IOS-1353713) and VE (IOS-1353857) and by the National Institutes of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) to AS (R01 AR070313). The University of Kentucky provided additional funding to AS.
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
This manuscript has been released as a pre-print at bioRxiv (104).
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2020.01695/full#supplementary-material It is also available for download as the additional file listed at the end of this record.
Gawriluk, Thomas R.; Simkin, Jennifer; Hacker, Corin K.; Kimani, John M.; Kiama, Stephen G.; Ezenwa, Vanessa O.; and Seifert, Ashley W., "Complex Tissue Regeneration in Mammals Is Associated with Reduced Inflammatory Cytokines and an Influx of T Cells" (2020). Biology Faculty Publications. 196.
Data sheet 1
Table_1_Complex Tissue Regeneration in Mammals Is Associated With Reduced Inflammatory Cytokines and an Influx of T Cells.XLSX (169 kB)
Table_2_Complex Tissue Regeneration in Mammals Is Associated With Reduced Inflammatory Cytokines and an Influx of T Cells.DOCX (35 kB)