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

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.

• Peng, W.
• Kepsch, A.
• Kracht, T. O.
• Hasan, H.
• Wijayarathna, R.
• Wahle, E.
• Pleuger, C.
• Bhushan, S.
• Günther, S.
• Kauerhof, A. C.
• Planinić, A.
• Fietz, D.
• Schuppe, H. C.
• Wygrecka, M.
• Loveland, K. L.
• Ježek, D.
• Meinhardt, A.
• Hedger, M. P.
• Fijak, M.