Immunoregulatory mechanisms between epithelial clear cells and mononuclear phagocytes in the epididymis

Abstract

IntroductionOne of the most intriguing aspects of male reproductive physiology is the ability of the epididymis to prevent the mounting of immune responses against the onslaught of foreign antigens carried by spermatozoa while initiating very efficient immune responses versus stressors. Epithelial clear cells are strategically positioned to work in a concerted manner with region‐specific heterogeneous subsets of mononuclear phagocytes to survey the epididymal barrier and regulate the balance between inflammation and immune tolerance in the post‐testicular environment.ObjectiveThis review aims to describe how clear cells communicate with mononuclear phagocytes to contribute to the unique immune environment in which sperm mature and are stored in the epididymis.Materials/methodsA comprehensive systematic review was performed. PubMed was searched for articles specific to clear cells, mononuclear phagocytes, and epididymis. Articles that did not specifically address the target material were excluded.ResultsIn this review, we discuss the unexpected roles of clear cells, including the transfer of new proteins to spermatozoa via extracellular vesicles and nanotubes as they transit along the epididymal tubule; and we summarize the immune phenotype, morphology, and antigen capturing, processing, and presenting abilities of mononuclear phagocytes. Moreover, we present the current knowledge of immunoregulatory mechanisms by which clear cells and mononuclear phagocytes may contribute to the immune‐privileged environment optimal for sperm maturation and storage.Discussion and conclusionNotably, we provide an in‐depth characterization of clear cell‐mononuclear phagocyte communication networks in the steady‐state epididymis and in the presence of injury. This review highlights crucial concepts of mucosal immunology and cellcell interactions, all of which are critical but understudied facets of human male reproductive health.

Three‐Dimensional Cell Culture of Epididymal Basal Cells and Organoids: A Novel Tool for Toxicology

“…Basal cells are present at the base of the epithelium, and halo cells, which include macrophages/monocytes, mononuclear phagocytes, and T lymphocytes, are also present in the epithelium (Fig. 1) (Battistone et al., 2023; Battistone et al., 2020; Breton et al., 2019; Robaire et al., 2015; Shum et al., 2013; Voisin et al., 2020).…”

Regional modulation of toll‐like receptor signaling pathway genes in acute epididymitis in mice

“…We detected a rapid increase in cJUN (Ser73) phosphorylation levels in the initial segment after LPS and LTA exposure.Moreover, LPS-and LTA-induced up-regulation of TLR-associated pathway genes was dependent on cJUN phosphorylation by JNKs in the initial segment, indicating an essential role of AP1 in inflammatory gene expression in the proximal epididymis. Conversely, we did not observe the inhibitory effect of SP600125 on the responses of the cauda epididymidis to LPS and LTA, indicating that AP1 is dispensable.The distinct relevance of NFKB and AP1 to inflammatory and immune gene expression in the initial segment and cauda epididymidis after LPS and LTA stimuli could be (i) associated with local differences in the immune microenvironments, including the diverse network of resident epithelial and interstitial immune cells, between these regions during acute inflammation,[4][5][6][7][8][9]23,[55][56][57] and (ii) secondary to changes in NFKB-and AP1-dependent circulating immune cell recruitment to the epididymis after PDCT and SP600125 treatments, respectively. Both scenarios are plausible since NFKB and AP1 are master regulators of cytokine and chemokine responses in immune and non-immune cells but also play vital roles in orchestrating the activation and recruitment of circulating immune cells, such as neutrophils and macrophages, to the injury site 15,20,24,25,[58][59][60].…”