Naslov
Activin A and CCR2 regulate macrophage function in testicular fibrosis caused by experimental autoimmune orchitis

Autori
Peng, Wei ; Kepsch, Artem ; Kracht, Till O. ; Hasan, Hiba ; Wijayarathna, Rukmali ; Wahle, Eva ; Pleuger, Christiane ; Bhushan, Sudhanshu ; Günther, Stefan ; Kauerhof, A. Christine ; Planinić, Ana ; Fietz, Daniela ; Schuppe, Hans- Christian ; Wygrecka, Małgorzata ; Loveland, Kate L. ; Ježek, Davor ; Meinhardt, Andreas ; Hedger, Mark P. ; Fijak, Monika

Izvornik
Cellular and molecular life sciences (1420-682X) 79 (2022), 12; 602, 24

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Activin A ; CCR2 ; CXCR4 ; EAO ; Fibrosis ; MMP2 ; Macrophages ; Testicular inflammation

Sažetak
Experimental 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.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

POVEZANOST RADA