Abstract
Infertility affects one in seven couples and ascending bacterial infections of the male genitourinary tract by Escherichia coli are an important cause of male factor infertility. Thus understanding mechanisms by which immunocompetent cells such as testicular macrophages (TM) respond to infection and how bacterial pathogens manipulate defense pathways is of importance. Whole genome expression profiling of TM and peritoneal macrophages (PM) infected with uropathogenic E. coli (UPEC) revealed major differences in regulated genes. However, a multitude of genes implicated in calcium signaling pathways was a common feature which indicated a role of calcium-dependent nuclear factor of activated T cells (NFAT) signaling. UPEC-dependent NFAT activation was confirmed in both cultured TM and in TM in an in vivo UPEC infectious rat orchitis model. Elevated expression of NFATC2-regulated anti-inflammatory cytokines was found in TM (IL-4, IL-13) and PM (IL-3, IL-4, IL-13). NFATC2 is activated by rapid influx of calcium, an activity delineated to the pore forming toxin alpha-hemolysin by bacterial mutant analysis. Alpha-hemolysin suppressed IL-6 and TNF-α cytokine release from PM and caused differential activation of MAP kinase and AP-1 signaling pathways in TM and PM leading to reciprocal expression of key pro-inflammatory cytokines in PM (IL-1α, IL-1β, IL-6 downregulated) and TM (IL-1β, IL-6 upregulated). In addition, unlike PM, LPS-treated TM were refractory to NFκB activation shown by the absence of degradation of IκBα and lack of pro-inflammatory cytokine secretion (IL-6, TNF-α). Taken together, these results suggest a mechanism to the conundrum by which TM initiate immune responses to bacteria, while maintaining testicular immune privilege with its ability to tolerate neo-autoantigens expressed on developing spermatogenic cells.
Highlights
Testicular macrophages (TM) represent the largest population of immune cells in the testis of mammals [1,2]
Our previous data using peritoneal macrophages (PM) and other studies have demonstrated the ability of Uropathogenic E. coli (UPEC) to suppress proinflammatory cytokine secretion in host cells [14,16,25]
Gene ontology documented a sustained upregulation of genes implicated in both anti- and pro-inflammatory response in TM, which was not visible in PM, a fact that could reflect the need for a more delicately balanced and fine tuned immune response at the interface between testicular immune privilege and anti-bacterial response
Summary
Testicular macrophages (TM) represent the largest population of immune cells in the testis of mammals [1,2]. UPEC alpha-hemolysin (HlyA) is a secreted pore forming toxin located on chromosomal PAIs. Integration of the toxin in the plasma membrane of host cells induces a rapid rise of cytoplasmic calcium levels through L-type calcium channels as well as from gated internal stores [21], an observation that stimulated by other agents is known to trigger downstream signaling cascades that lead to activation of important transcription factors including CREB, NFkB and NFAT [22,23]. We showed that UPEC actively suppress MyD88-dependent Toll-like receptor signaling to prevent secretion of certain pro-inflammatory cytokines by testicular somatic cells including TM, a mechanism that facilitates pathogens survival and their detrimental actions on male fertility [16]. The objective of this study was (i) to elucidate the molecular details vital in this process set in comparison with another type of macrophage known to mount classical responses to pathogens such as peritoneal macrophages (PM) and (ii) to unravel UPEC virulence factors crucial in suppression of a pro-inflammatory immune response directed against the pathogen
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