Abstract
Mumps virus (MuV) infection usually results in germ cell degeneration in the testis, which is an etiological factor for male infertility. However, the mechanisms by which MuV infection damages male germ cells remain unclear. The present study showed that C-X-C motif chemokine ligand 10 (CXCL10) is produced by mouse Sertoli cells in response to MuV infection, which induces germ cell apoptosis through the activation of caspase-3. CXC chemokine receptor 3 (CXCR3), a functional receptor of CXCL10, is constitutively expressed in male germ cells. Neutralizing antibodies against CXCR3 and an inhibitor of caspase-3 activation significantly inhibited CXCL10-induced male germ cell apoptosis. Furthermore, the tumor necrosis factor-α (TNF-α) upregulated CXCL10 production in Sertoli cells after MuV infection. The knockout of either CXCL10 or TNF-α reduced germ cell apoptosis in the co-cultures of germ cells and Sertoli cells in response to MuV infection. Local injection of MuV into the testes of mice confirmed the involvement of CXCL10 in germ cell apoptosis in vivo. These results provide novel insights into MuV-induced germ cell apoptosis in the testis.
Highlights
More than 50% of patients with bilateral mumps orchitis experience infertility.[2]
Sertoli and germ cells were identified by staining with luteinizing hormone receptor (LHR), Wilms tumor nuclear protein 1 (WT1) and mouse VASA homolog (MVH), respectively (Figure 1a)
This study demonstrated that the CXCL10 produced by Sertoli cells in response to MuV infection induces germ cell apoptosis and tumor necrosis factor-α (TNF-α) upregulates CXCL10 production in an autocrine manner
Summary
More than 50% of patients with bilateral mumps orchitis experience infertility.[2]. a major pathological manifestation of mumps orchitis is germ cell degeneration.[3]. Several inflammatory cytokines are involved in testis pathophysiology.[5] Interleukin 1 (IL-1), IL-6 and tumor necrosis factor-α (TNF-α) have important roles in regulating spermatogenesis under physiological conditions.[6] These cytokines can be upregulated and impair testicular functions under inflammatory conditions.[7] High levels of IL-1, IL-6 and TNF-α inhibit steroidogenesis in Leydig cells.[8,9,10] TNF-α upregulation induced male germ cells apoptosis in an experimental autoimmune orchitis model.[11] We recently demonstrated that the C-X-C motif chemokine ligand 10 (CXCL10) expression is remarkably upregulated in Leydig and Sertoli cells in response to MuV infection,[12] but the effect of the increased CXCL10 on testicular function remains unknown. We recently demonstrated that MuV dramatically induces CXCL10 expression in mouse Leydig and Sertoli cells but not in germ cells.[12]
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