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

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

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8 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number602
Number of pages24
JournalCellular and Molecular Life Sciences
Volume79
Issue number12
DOIs
Publication statusPublished - Dec 2022

Keywords

  • Activin A
  • CCR2
  • CXCR4
  • EAO
  • Fibrosis
  • Macrophages
  • MMP2
  • Testicular inflammation

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