Toll-like receptors and signalling in spermatogenesis and testicular responses to inflammation—a perspective

Abstract

It is self-evident that infection and inflammation in the reproductive tract can inhibit male fertility, but the observation that fertility may also be compromised by systemic inflammation and disease is more difficult to explain. Recent studies implicating microbial pattern-recognition receptors, such as the Toll-like receptors (TLRs), as well as inflammatory cytokines and their signalling pathways, in testicular function have cast new light on this mysterious link between infection/inflammation and testicular dysfunction. It is increasingly evident that signalling pathways normally involved in controlling inflammation play fundamental roles in regulating Sertoli cell activity and responses to reproductive hormones, in addition to promoting immune responses within the testis. Many of the negative effects of inflammation on spermatogenesis may be attributed to elevated production of inflammation-related gene products within the circulation and the testis, which subsequently exert disruptive effects on spermatogenic cell development and survival, as well as the ability of the Sertoli cells to provide support for spermatogenesis. These interactions have important implications for testicular dysfunction and disease, and may eventually provide new opportunities for therapeutic interventions.

The effect of secondary cholestasis on the CD68-positive and CD163-positive macrophage population, cellular proliferation, and apoptosis in rat testis

“…In cirrhotic patients, the up-regulation of TLR2 and TLR4 expression in blood monocytes can also be observed (Pimentel-Nunes et al, 2011). When the TLR2 and TLR4 receptor complex stimulated by bacterial lipopeptide and LPS respectively, the subsequent activation of the inflammatory transcription factors such as nuclear factor kappa B, activate protein 1, Jun N-terminal kinase, and p38 mitogen-activated protein kinases, can induce the expression of pro-inflammatory cytokines (Hedger, 2011;Riccioli et al, 2006), which can cause testicular inflammation and may directly inhibit Leydig cell function, resulting in low blood testosterone. The possible pathogenesis is as follows.…”

“…The precise mechanisms responsible for this inhibition remain unclear and are probably multifactorial, i.e., infection (Adamopoulos et al, 1978;Buch and Havlovec, 1991), inflammation (Hedger, 2011;Kajihara et al, 2006;Liew et al, 2007;O'Bryan et al, 2000), reactive oxygen species (Aly et al, 2012;Gavazza and Catala, 2003;Reddy et al, 2006), proinflammatory cytokine release (Gerdprasert et al, 2002;Riccioli et al, 2006), excessive infiltration of inflammatory cells (Gerdprasert et al, 2002;Hedger, 2002;O'Bryan et al, 2000), and necrotic cell death and apoptosis (Metukuri et al, 2010).…”

Testicular defense systems: immune privilege and innate immunity

“…103 Functional TLRs were initially demonstrated within murine SCs, showing that TLR2 and TLR4 signaling can be initiated by their ligands. 102 TLR expression was then further defined in male rat reproductive tracts and testicular cells.…”

Damaged spermatogenic cells induce inflammatory gene expression in mouse Sertoli cells through the activation of Toll-like receptors 2 and 4

“…In contrast to testicular inflammation due to infectious origin, the mechanisms underlying the initiation of noninfectious inflammation in the testis are poorly understood. Involvement of Toll-like receptors (TLRs) in testicular innate immune responses to alloantigens has been recently revealed (Hedger, 2011). In the present study, we investigate roles of TLRs in noninfectious testicular inflammation in response to spermatogenic cell damage that may occur in some pathological conditions.…”