Peng, WeiWeiPengKepsch, ArtemArtemKepschKracht, Till O.Till O.KrachtHasan, HibaHibaHasanWijayarathna, RukmaliRukmaliWijayarathnaWahle, EvaEvaWahlePleuger, ChristianeChristianePleugerBhushan, SudhanshuSudhanshuBhushanGünther, StefanStefanGüntherKauerhof, A. ChristineA. ChristineKauerhofPlaninic, AnaAnaPlaninicFietz, DanielaDanielaFietzSchuppe, Hans-ChristianHans-ChristianSchuppeWygrecka, MalgorzataMalgorzataWygreckaLoveland, Kate L.Kate L.LovelandJežek, DavorDavorJežekMeinhardt, AndreasAndreasMeinhardtHedger, Mark P.Mark P.HedgerFijak, MonikaMonikaFijak2023-11-152023-11-152022https://jlupub.ub.uni-giessen.de/handle/jlupub/18663http://dx.doi.org/10.22029/jlupub-18027Experimental autoimmune-orchitis (EAO), a rodent model of chronic testicular inflammation and fibrosis, replicates pathogenic changes seen in some cases of human spermatogenic disturbances. During EAO, increased levels of pro-inflammatory and pro-fibrotic mediators such as TNF, CCL2, and activin A are accompanied by infiltration of leukocytes into the testicular parenchyma. Activin A levels correlate with EAO severity, while elevated CCL2 acting through its receptor CCR2 mediates leukocyte trafficking and recruits macrophages. CCR2 + CXCR4 + macrophages producing extracellular matrix proteins contribute widely to fibrogenesis. Furthermore, testicular macrophages (TMs) play a critical role in organ homeostasis. Therefore, we aimed to investigate the role of the activin A/CCL2-CCR2/macrophage axis in the development of testicular fibrosis. Following EAO induction, we observed lower levels of organ damage, collagen deposition, and leukocyte infiltration (including fibronectin+, collagen I+ and CXCR4+ TMs) in Ccr2−/− mice than in WT mice. Furthermore, levels of Il-10, Ccl2, and the activin A subunit Inhba mRNAs were lower in Ccr2−/− EAO testes. Notably, fibronectin+ TMs were also present in biopsies from patients with impaired spermatogenesis and fibrotic alterations. Overexpression of the activin A antagonist follistatin reduced tissue damage and collagen I+ TM accumulation in WT EAO testes, while treating macrophages with activin A in vitro increased the expression of Ccr2, Fn1, Cxcr4, and Mmp2 and enhanced migration along a CCL2 gradient; these effects were abolished by follistatin. Taken together, our data indicate that CCR2 and activin A promote fibrosis during testicular inflammation by regulating macrophage function. Inhibition of CCR2 or activin A protects against damage progression, offering a promising avenue for therapeutic intervention.enNamensnennung 4.0 InternationalTesticular inflammationFibrosisEAOMacrophagesCCR2Activin ACXCR4MMP2ddc:610