Lipopolysaccharide and lipotheicoic acid differentially modulate epididymal cytokine and chemokine profiles and sperm parameters in experimental acute epididymitis

Abstract

Bacterial infections are the most prevalent etiological factors of epididymitis, a commonly diagnosed inflammatory disease in the investigation of male infertility factors. The influence of early pathogenic mechanisms at play during bacterial epididymitis on reproductive outcomes is little understood. We report here that experimental epididymitis induced in rats by Gram-negative (LPS) and Gram-positive (LTA) bacterial products resulted in differential patterns of acute inflammation in the cauda epididymis. LPS elicited a strong inflammatory reaction, as reflected by upregulation of levels of mRNA for seven inflammatory mediators (Il1b, Tnf, Il6, Ifng, Il10, Nos2 and Nfkbia), and tissue concentration of six cytokines/chemokines (IL1A, IL1B, IL6, IL10, CXCL2 and CCL2) within the first 24 h post-treatment. Conversely, LTA induced downregulation of one (Nfkbia) and upregulation of six (Il1b, Il6, Nos2, Il4 Il10 and Ptgs1) inflammatory gene transcripts, whereas increased the tissue concentration of three cytokines/chemokines (IL10, CXCL2 and CCL2). The stronger acute inflammatory response induced by LPS correlated with a reduction of epididymal sperm count and transit time that occurred at 1, 7, and 15 days post-treatment. Our study provides evidence that early epididymal inflammatory signaling events to bacterial activators of innate immunity may contribute to the detrimental effects of epididymitis upon male fertility.

In search of new paradigms for epididymal health and disease: innate immunity, inflammatory mediators, and steroid hormones

“…They act as the first barrier in the defense against a wide range of challenges (infectious and non‐infectious) and are critically involved in the regulation of both innate and adaptive immune responses. For example, basal levels of Toll ‐like receptor 4 (TLR4), which is the major receptor for bacterial lipopolysaccharide (LPS) in mammalian cells, and its downstream signaling molecules that lead to nuclear factor kB (NFKB) activation, are found in normal conditions within the epididymis along with basal levels of NFKB‐dependent inflammatory genes, such as Il1b (interleukin 1 beta), Tnf (tumor necrosis factor alpha), Nfkbia (NFKB inhibitor alpha) (Palladino et al ., ; Rodrigues et al ., ; Silva et al ., ). Drawing from in vivo and in vitro studies, epididymal TLR4 activation by LPS leads to a robust upregulation of NFKB‐dependent inflammatory gene expression as part of the tissue response to this inflammatory stimulus (Rodrigues et al ., ; Silva et al ., ; Lang et al ., ).…”

“…Drawing from in vivo and in vitro studies, epididymal TLR4 activation by LPS leads to a robust upregulation of NFKB‐dependent inflammatory gene expression as part of the tissue response to this inflammatory stimulus (Rodrigues et al ., ; Silva et al ., ; Lang et al ., ). The functional expression of more TLRs (TLR2, TLR3, TLR5, TLR6, among others) that respond to different types of pathogens have also been reported in the epididymis (Browne et al ., ; Cheng et al ., ; Silva et al ., ). A variety of cytokines and their cognate receptors is present in the epididymis (Politch et al ., ; Zhao et al ., ; Turner et al ., ; Jrad‐Lamine et al ., ; Wei et al ., ; Silva et al ., ; Fig.…”

“…The functional expression of more TLRs (TLR2, TLR3, TLR5, TLR6, among others) that respond to different types of pathogens have also been reported in the epididymis (Browne et al ., ; Cheng et al ., ; Silva et al ., ). A variety of cytokines and their cognate receptors is present in the epididymis (Politch et al ., ; Zhao et al ., ; Turner et al ., ; Jrad‐Lamine et al ., ; Wei et al ., ; Silva et al ., ; Fig. ).…”

“…() and Silva et al . (). (A) Inflammatory cytokines, such as IL 1A, IL 1B, IL 2, IL 4, IL 6, IL 10, IL 17, TNF , CSF , IFNG , IFNA , IFNB , CCL 2, CCL 5, and CCXCL 2, are constitutively found in control cauda epididymis.…”

Expression profile of Toll‐like receptor 4 in rat testis and epididymis throughout postnatal development

“…Bacterial infections are the most frequent etiological factors of male genital tract. Researchers showed that lipopolysaccharides (LPS), major components of the outer membrane of Gram-negative bacteria, induced epididymitis (Michel, Pilatz, Hedger, & Meinhardt, 2015;Silva et al, 2018). However, autoimmune orchitis can occur under certain pathological conditions, such as physical trauma, and exposure to chemical toxins or high temperature that may damage germ cells (Schuppe et al, 2008).…”