Novel role of proton-secreting epithelial cells in sperm maturation and mucosal immunity

Abstract

Epithelial cells are immune sensors and mediators that constitute the first line of defense against infections. Using the epididymis, a model for studying tubular organs, we uncovered a novel and unexpected role for professional proton-secreting 'clear cells' in sperm maturation and immune defense. The epididymal epithelium participates in the maturation of spermatozoa via the establishment of an acidic milieu and transfer of proteins to sperm cells, a poorly characterized process. We show that proton-secreting clear cells express mRNA transcripts and proteins that are acquired by maturing sperm, and that they establish close interactions with luminal spermatozoa via newly described 'nanotubes'. Mechanistic studies show that injection of bacterial antigens in vivo induces chemokine expression in clear cells, followed by macrophage recruitment into the organ. Injection of an inflammatory intermediate mediator (IFN-γ) increased Cxcl10 expression in clear cells, revealing their participation as sensors and mediators of inflammation. The functional diversity adopted by clear cells might represent a generalized phenomenon by which similar epithelial cells decode signals, communicate with neighbors and mediate mucosal immunity, depending on their precise location within an organ.This article has an associated First Person interview with the first author of the paper.

Spatio-temporal landscape of mouse epididymal cells and specific mitochondria-rich segments defined by large-scale single-cell RNA-seq

“…Compared to the principal cells, the functions of other cell types are less known. Clear/narrow cells were reported to be involved in proton secretion with the expression of H + -ATPase 2 , 48 . Basal cells were proposed to participate in the endocrine or paracrine regulation of principal cells 49 .…”

Differential Immune Response to Infection and Acute Inflammation Along the Epididymis

“…All of them were found in the top 50 significantly differential expressed genes with high baseline expression in the normal caput epididymis using whole transcriptome analysis ( 14 ). While beta-defensins are mostly expressed by epithelial cells, including proton-secreting clear cells with protrusions reaching into the lumen ( 53 ) for other anti-microbial peptides their cellular origin in the epididymis is not established, e.g. those controlling infection with gram-negative bacteria ( Lcn2 , Lypd8 ).…”

Acrylamide modulates the mouse epididymal proteome to drive alterations in the sperm small non-coding RNA profile and dysregulate embryo development

“…However, consistent with other observations (Rompala et al, 2018) this form of communication does not account for the trafficking of all responsive sncRNAs. Association with RNA-binding proteins, as seen with other mammalian cells (Arroyo et al, 2011;Wang et al, 2010) and/or nanotubes may represent additional trafficking mechanisms that contribute to shaping the sperm sncRNA profile following stress exposure (Battistone et al, 2019). It will, therefore, clearly be of value to refine our mechanistic understanding of how other sncRNA species (namely the tRF and piRNA sncRNA species) are modulated in response to paternal stress and trafficked to spermatozoa.…”