UropathogenicEscherichia coliBlock MyD88-Dependent and Activate MyD88-Independent Signaling Pathways in Rat Testicular Cells

Abstract

Uropathogenic Escherichia coli (UPEC) is the most common etiological cause of urogenital tract infections and represents a considerable cause of immunological male infertility. We examined TLR 1–11 expression profiles in testicular cells and the functional response to infection with UPEC. All testicular cell types expressed mRNAs for at least two TLRs and, in particular, synthesis of TLR4 was induced in testicular macrophages (TM), Sertoli cells (SC), peritubular cells (PTC), and peritoneal macrophages (PM) after UPEC exposure. Even though MyD88-dependent pathways were activated as exemplified by phosphorylation of mitogen-activated protein kinases in TM, SC, PTC, and PM and by the degradation of IκBα and the nuclear translocation of NF-κB in PTC and PM, treatment with UPEC did not result in secretion of the proinflammatory cytokines IL-1α, IL-6, and TNF-α in any of the investigated cells. Moreover, stimulated production of these cytokines by nonpathogenic commensal E. coli or LPS in PM was completely abolished after coincubation with UPEC. Instead, in SC, PTC, TM, and PM, UPEC exposure resulted in activation of MyD88-independent signaling as documented by nuclear transfer of IFN-related factor-3 and elevated expression of type I IFNs α and β, IFN-γ-inducible protein 10, MCP-1, and RANTES. We conclude that in this in vitro model UPEC can actively suppress MyD88-dependent signaling at different levels to prevent proinflammatory cytokine secretion by testicular cells. Thus, testicular innate immune defense is shifted to an antiviral-like MyD88-independent response.

Testicular defense systems: immune privilege and innate immunity

“…113 Other NLRs are involved in the processing and activation of inflammatory cytokines, including IL-1b and IL-18, which are activators of inflammasomes. 114 Both NOD1 and NOD2 mRNAs were detected in some testicular cells, including SCs and germ cells, 105 but their functions in these cells have not been examined. Many NLR members are involved in immune modulation as inflammasome activators.…”

“…84,85 Different stages of germ cells also express TLRs. 105 We recently demonstrated that TLR3 in spermatogonia and spermatocytes and TLR11 in spermatids initiate innate immune responses. 108,109 The TLR-initiated innate immune responses in male germ cells are particularly interesting because the germ cells represent a majority of the testicular cell population.…”

“…102 TLR expression was then further defined in male rat reproductive tracts and testicular cells. 104,105 The functions of more TLRs, including TLR3, TLR5 and TLR6, were investigated in mouse SCs by our group and by other researchers. 106,107 TLRs initiate the innate immune response in SCs by inducing immunoregulatory cytokines, including TNF-a, IL-1, IL-6, MCP-1 and type 1 IFNs (Table 1).…”

Innate immunity in the male genital tract: Chlamydia trachomatis induces keratinocyte-derived chemokine production in prostate, seminal vesicle and epididymis/vas deferens primary cultures

“…Expression of TLR2-6 mRNA in mouse Sertoli cells and subsequent activation of the NF-kB pathway following stimulation with TLR2 and TLR5 agonists were demonstrated by Riccioli et al (2006). Bhushan et al (2008) demonstrated that all testicular cell types expressed mRNAs of one to six TLRs, and, in particular, TLR3 transcription was evident in all testicular cells, suggesting a strong capacity for the recognition of double-stranded viral RNA in the testes.…”

Testicular innate immune defense against bacteria

“…It is only recently that expression of TLR 1-11 was shown in total rat testis, epididymis and vas deferens (Palladino et al, 2007) and of TLR 1-9 in human testis samples (Nishimura & Naito, 2005). Riccioli et al (Riccioli et al, 2006) A c c e p t e d M a n u s c r i p t 8 weak expression was evident (Bhushan et al, 2008). This indicates a strong capacity of recognizing double stranded viral RNA in the testis.…”