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There is a need for alternative approaches to inhibit CD40 that avoid these complications. CD40 signals through TRAF2,3 and TRAF6\u2010binding sites. Given that CD40\u2010TRAF6 is the pathway that stimulates responses key for cell\u2010mediated immunity against opportunistic pathogens, we examined the effects of pharmacologic inhibition of CD40\u2010TRAF2,3 signaling. We used a model of ischemia\/reperfusion (I\/R)\u2010induced retinopathy, a CD40\u2010driven inflammatory disorder. Intravitreal administration of a cell\u2010penetrating CD40\u2010TRAF2,3 blocking peptide impaired ICAM\u20101 upregulation in retinal endothelial cells and CXCL1 upregulation in endothelial and M\u00fcller cells. The peptide reduced leukocyte infiltration, upregulation of NOS2\/COX\u20102\/TNF\u2010\u03b1\/IL\u20101\u03b2, and ameliorated neuronal loss, effects that mimic those observed after I\/R in Cd40\u2212\/\u2212 mice. While a cell\u2010penetrating CD40\u2010TRAF6 blocking peptide also diminished I\/R\u2010induced inflammation, this peptide (but not the CD40\u2010TRAF2,3 blocking peptide) impaired control of the opportunistic pathogen\n                    <jats:italic>Toxoplasma gondii<\/jats:italic>\n                    in the retina. Thus, inhibition of the CD40\u2010TRAF2,3 pathway is a novel and potent approach to reduce CD40\u2010induced inflammation, while likely diminishing the risk of opportunistic infections that would otherwise accompany CD40 inhibition.\n                  <\/jats:p>","DOI":"10.1096\/fj.201903203rr","type":"journal-article","created":{"date-parts":[[2021,3,6]],"date-time":"2021-03-06T07:03:56Z","timestamp":1615014236000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A cell\u2010penetrating CD40\u2010TRAF2,3 blocking peptide diminishes inflammation and neuronal loss after ischemia\/reperfusion"],"prefix":"10.1096","volume":"35","author":[{"given":"Jose\u2010Andres C.","family":"Portillo","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases and HIV Medicine, Department of Medicine Case Western Reserve University School of Medicine Cleveland OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin\u2010Sang","family":"Yu","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and HIV Medicine, Department of Medicine Case Western Reserve University School of Medicine Cleveland OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel","family":"Hansen","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and HIV Medicine, Department of Medicine Case Western Reserve University School of Medicine Cleveland OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy S.","family":"Kern","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Case Western Reserve University School of Medicine Cleveland OH USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. 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