Microcystin-leucine arginine exhibits immunomodulatory roles in testicular cells resulting in orchitis

Microcystin-leucine arginine (MC-LR) causes testicular inflammation and hinders spermatogenesis. However, the molecular mechanisms underlying the immune responses to MC-LR in the testis have not been elucidated in detail. In this study, we show that MC-LR induced immune responses in Sertoli cells (SC), germ cells (GC), and Leydig cells (LC) via activating phosphatidylinositol 3-kinase (PI3K)/Akt/nuclear factor kappa B (NF-κB), resulting in the production of pro-inflammatory cytokines and chemokines including tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and chemokine (C-X-C motif) ligand 10 (CXCL10). The observed effects were attributed to reduced activity of protein phosphatases 2A (PP2A) as a result of binding of MC-LR to the catalytic subunit of PP2A in SC and GC. By contrast, innate immune responses were triggered by Toll-like Receptor 2 (TLR2) in LC because MC-LR could not enter into the LC and subsequently inhibit the PP2A activity. PI3K/Akt/NF-κB were also activated in SC, GC, and LC in vivo, with the enrichment of TNF-α, IL-6, MCP-1, and CXCL10 in the testis. Following chronic exposure, MC-LR-treated mice exhibited decreased sperm counts and abnormal sperm morphology. Our data demonstrate that MC-LR can activate innate immune responses in testicular cells, which provides novel insights to explore the mechanism associated with MC-LR-induced orchitis.