Sertoli cells have a functional NALP3 inflammasome that can modulate autophagy and cytokine production

Abstract

Sertoli cells, can function as non-professional tolerogenic antigen-presenting cells, and sustain the blood-testis barrier formed by their tight junctions. The NOD-like receptor family members and the NALP3 inflammasome play a key role in pro-inflammatory innate immunity signalling pathways. Limited data exist on NOD1 and NOD2 expression in human and mouse Sertoli cells. Currently, there is no data on inflammasome expression or function in Sertoli cells. We found that in primary pre-pubertal Sertoli cells and in adult Sertoli line, TLR4\NOD1 and NOD2 crosstalk converged in NFκB activation and elicited a NALP3 activation, leading to de novo synthesis and inflammasome priming. This led to caspase-1 activation and IL-1β secretion. We demonstrated this process was controlled by mechanisms linked to autophagy. NOD1 promoted pro-IL-1β restriction and autophagosome maturation arrest, while NOD2 promoted caspase-1 activation, IL-1β secretion and autophagy maturation. NALP3 modulated NOD1 and pro-IL-1β expression, while NOD2 inversely promoted IL-1β. This study is proof of concept that Sertoli cells, upon specific stimulation, could participate in male infertility pathogenesis via inflammatory cytokine induction.

Molecular Mechanisms and Signaling Pathways Involved in Sertoli Cell Proliferation

“…Interleukin 1 (IL-1) exists as two major agonist isotypes, IL-1α, and IL-1β, and these cytokines have a naturally antagonist named IL-1 receptor antagonist (IL-1ra). In rodent testis, IL-1α, and IL-1β are produced by Sertoli cells, interstitial macrophages and Leydig cells (111–115). The production of IL-1α by human Sertoli and Leydig cells has also been demonstrated (116).…”

Prokineticin 2 via Calcium-Sensing Receptor Activated NLRP3 Inflammasome Pathway in the Testicular Macrophages of Uropathogenic Escherichia coli-Induced Orchitis

“…NLRP3 and ASC promote the cleavage of pro-caspase-1 and form an active complex, which triggers the cleavage of pro-IL-1b into mature IL-1b (9). In a murine model of UPEC orchitis, NLRP3, ASC, caspase-1, and IL-1b are clearly elevated in TM (10)(11)(12).…”

Association of Seminal Plasma Level of NLRP3 Inflammasome Protein with Quality of Seminal Fluid Parameters Among Infertile Men

“…They depend on enzymes (16) and cytokines (17) that participate in inflammatory process of male genitalia (14) . Group of researchers highlighted the importance of inflammasome protein NLRP3 as a "physiological low level of inflammation" for fertility (6).It had been suggested that low level of NLRP3 is essential for Sertoli cell production of low levels of IL1B to maintain IL1 alpha (18) but higher rate of inflammasome expression will results in higher level of inflammasome activation cytokines such as IL-1B and IL-18 (19) and served as a proinflammatory signals generating an inflammatory process in the testis such as leucocyte infiltration and cell death signaling and caspase 1 activation (20)(21)(22) .Also, it might activate ASC adaptor protein in both sperm cell and leucocytes in semen resulting in inflammatory cell death (23) . To date, the primary focus of inflammasome research has been anchored by NLRP3, which is a cytoplasmic protein that is primarily expressed in monocytes, macrophages, granulocytes, dendritic cells, epithelial cells and osteoblasts (24).…”

“…To date, the primary focus of inflammasome research has been anchored by NLRP3, which is a cytoplasmic protein that is primarily expressed in monocytes, macrophages, granulocytes, dendritic cells, epithelial cells and osteoblasts (24). NLRP3 expression in myeloid cells is highly inducible (25) and other epithelial and Sertoli cells (6). So, the leukocyte counting is not always giving a true picture of inflammation, because of wide range of cells have the ability to respond and considered as a source of inflammatory mediators.…”

“…NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome is a multiprotein complex that orchestrates innate immune responses to infection and cell stress through activation of caspase-1 and maturation of inflammatory cytokines (1).NLRP3 has also been implicated in the pathogenesis of many diseases including arthropathy, ischemic heart and renal disease, vascular disease, diabetes and obesity, Alzheimer's dementia, and others, which are well-reviewed elsewhere (2). It has shown that inflammasome activation and the consequent elevation of seminal proinflammatory cytokines leads to impaired sperm motility in men with spinal cord injury (SCI) (3) and non-SCI men (4)(5)(6) .Suggesting leukocyte activation may be key to a relationship between inflammation and infertility (7)(8)(9) .Cytokines affect Sertoli cell function, and alterations in cytokine levels in the testis could affect spermatogenesis. One of the mechanisms by which leukocytospermia may lead to sperm dysfunction is related to sperm damage induced by reactive oxygen species (ROS) via activated leukocytes during or after ejaculation (7,10) .…”