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Inflammation is essential for effective innate immune\u2010cell recruitment; however, excessive inflammation will result in local tissue destruction, pathogen egress, and ineffective pathogen clearance. Sterile and nonsterile inflammation operate with competing functional priorities but share common receptors and overlapping signal transduction pathways. In regenerative organisms such as the salamander, whole limbs can be replaced after amputation while exposed to a nonsterile environment. In mammals, exposure to sterile\u2010injury Damage Associated Molecular Patterns (DAMPS) alters innate immune\u2010cell responsiveness to secondary Pathogen Associated Molecular Pattern (PAMP) exposure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Using new phospho\u2010flow cytometry techniques to measure signaling in individual cell subsets we compared mouse to salamander inflammation. These studies demonstrated evolutionarily conserved responses to PAMP ligands through toll\u2010like receptors (TLRs) but identified key differences in response to DAMP ligands. Co\u2010exposure of macrophages to DAMPs\/PAMPs suppressed MAPK signaling in mammals, but not salamanders, which activate sustained MAPK stimulation in the presence of endogenous DAMPS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results reveal an alternative signal transduction network compatible with regeneration that may ultimately lead to the promotion of enhanced tissue repair in mammals.<\/jats:p><\/jats:sec>","DOI":"10.1002\/dvdy.340","type":"journal-article","created":{"date-parts":[[2021,4,1]],"date-time":"2021-04-01T21:39:20Z","timestamp":1617313160000},"page":"988-1003","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Distinct toll\u2010like receptor signaling in the salamander response to tissue damage"],"prefix":"10.1002","volume":"251","author":[{"given":"Ryan J.","family":"Debuque","sequence":"first","affiliation":[{"name":"Australian Regenerative Medicine Institute (ARMI) Monash University  Melbourne Victoria Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergej","family":"Nowoshilow","sequence":"additional","affiliation":[{"name":"The Research Institute of Molecular Pathology (IMP)  Vienna Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katya E.","family":"Chan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadia A.","family":"Rosenthal","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory  Bar Harbour Maine USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9234-7807","authenticated-orcid":false,"given":"James W.","family":"Godwin","sequence":"additional","affiliation":[{"name":"Australian Regenerative Medicine Institute (ARMI) Monash University  Melbourne Victoria Australia"},{"name":"The Jackson Laboratory  Bar Harbour Maine USA"},{"name":"The MDI Biological 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