Sertoli cell-initiated testicular innate immune response through toll-like receptor-3 activation is negatively regulated by Tyro3, Axl, and mer receptors.
Several Toll-like receptors (TLRs) are expressed in Sertoli cells and can trigger testicular innate responses after activation by ligands. TLR signaling pathway must be tightly controlled because unrestrained TLR activation generates a chronic inflammatory milieu that often leads to pathogenesis of the host. However, the regulation of TLR signaling in Sertoli cells remains to be clarified. Here we demonstrate that Tyro3 subfamily of receptor tyrosine kinases, Tyro3, Axl, and Mer (TAM), negatively regulate TLR3 signaling in Sertoli cells. Sertoli cells from TAM triple mutant (TAM(-/-)) mice exhibit an excessive activation of TLR3 in response to its ligand polyinosinic-polycytidylic acid, resulting in the up-regulation of inflammatory cytokines including IL-1beta, IL-6, TNFalpha, and type I interferons (alpha and beta). Growth arrest-specific gene 6 (Gas6), a common ligand of TAM receptors, inhibits the TLR3-driven expression of cytokines in Sertoli cells. This TAM-mediated inhibition of TLR3 signaling in Sertoli cells is transduced through the up-regulation of TLR signaling suppressors suppressor of cytokine signaling-1/3 by Gas6. Moreover, we provide evidence that TAM inhibition of inflammatory cytokine production by Sertoli cells may have physiological significance in vivo. These results illuminate a negative regulatory mechanism of TLR3 signaling in Sertoli cells, which may participate in controlling the testicular innate immune responses to pathogens.
Sun
Bing
B
Department of Cell Biology, Peking Union Medical College and Chinese Academy of Medical Sciences, 5 Dong Dan San Tiao, Beijing 100005, People's Republic of China.
Qi
Nan
N
Shang
Tao
T
Wu
Hui
H
Deng
Tingting
T
Han
Daishu
D
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D019084:Fluorescent Antibody Technique, Indirect; D007150:Immunohistochemistry; D007370:Interferon Type I / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D011070:Poly I-C / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D012708:Sertoli Cells / Q000187:drug effects / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase
D007370:Interferon Type I; D053583:Interleukin-1beta; D015850:Interleukin-6; D011518:Proto-Oncogene Proteins; D051196:Toll-Like Receptor 3; D014409:Tumor Necrosis Factor-alpha; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; C513478:Tyro3 protein, mouse; D000076202:c-Mer Tyrosine Kinase; D011070:Poly I-C; D000094963:Axl Receptor Tyrosine Kinase; C000722290:AXL receptor tyrosine kinase, mouse