Activation of the NLRP3 Inflammasome Pathway by Prokineticin 2 in Testicular Macrophages of Uropathogenic Escherichia coli- Induced Orchitis

Abstract

Infections of the reproductive tract are known to contribute to testicular inflammatory impairment, leading to an increase of pro-inflammatory cytokines such as IL-1β, and a decline in sperm quality. Prokineticin 2 (PK2), a secretory protein, is closely associated with the secretion of pro-inflammatory cytokines in inflamed tissue. It was reported that increased PK2 is related to the upregulation of IL-1β, but the underlying mechanism remains elusive. Here, we illustrated that PK2 was upregulated in testicular macrophages (TM) in a rat model of uropathogenic Escherichia coli (UPEC) infection, which induced the activation of the NLRP3 inflammasome pathway to boost IL-1β secretion. Administration of PK2 inhibitor alleviated the inflammatory damage and suppressed IL-1β secretion. Moreover, PK2 promoted NLRP3 expression and the release of cleaved IL-1β from TM to the supernatants after the challenge with UPEC in vitro . IL-1β in the supernatants affected Leydig cells by suppressing the expression of genes encoding for the enzymes P450scc and P450c17, which are involved in testosterone production. Overall, we revealed that increased PK2 levels in TM in UPEC-induced orchitis may impair testosterone synthesis via the activation of the NLRP3 pathway. Our study provides a new insight into the mechanisms underlying inflammation-associated male infertility and suggests an anti-inflammatory therapeutic target for male infertility.

Prokineticin 2 via Calcium-Sensing Receptor Activated NLRP3 Inflammasome Pathway in the Testicular Macrophages of Uropathogenic Escherichia coli-Induced Orchitis

“…LPS and bacterial DNA directly stimulate the upregulation of PK2 in Raw 264.7 cells (34). After UPEC infection, PK2 induces the activation of the NLRP3 inflammasome through the MAPK pathway, thereby promoting the maturation of IL-1b (12). This finding is consistent with our findings.…”

“…the NLRP3 inflammasome (12). Despite that NLRP3 and inflammation-related IL-1b are upregulated in UPEC-infected TM, whether CaSR induces NLRP3 inflammasome activity in the pathogenesis of orchitis is unclear.…”

“…Given the potential relationship between CaSR and NLRP3, we concluded that CaSR is closely related to UPEC-induced testicular inflammation. Based on our previous findings that PK2 promotes IL-1b secretion through the NLRP3 pathway (12), we speculated that PK2 and CaSR have a close relationship. In this study, we focused on the effect of CaSR on IL-1b secretion in TM during a UPEC infection to reveal the molecular mechanism that may ultimately damage male fertility.…”

“…NLRP3 and ASC promote the cleavage of pro-caspase-1 and form an active complex, which triggers the cleavage of pro-IL-1b into mature IL-1b (9). In a murine model of UPEC orchitis, NLRP3, ASC, caspase-1, and IL-1b are clearly elevated in TM (10)(11)(12).…”

Identification of crucial genes mediating abdominal aortic aneurysm pathogenesis based on gene expression profiling of perivascular adipose tissue by WGCNA

“…PROK2 is upregulated in granulocytes and macrophages found in inflamed tissue (44). Previous studies suggest that PROK2 plays important roles in mediating inflammation-associated disorders, such as inflammatory pain, psoriasis, and orchitis (44)(45)(46). Choke et al also found that PROK2 was upregulated with 7-fold at rupture sites of AAA (47).…”