T cell Ig mucin-3 promotes homeostasis of sepsis by negatively regulating the TLR response.
Sepsis is an excessive inflammatory condition with a high mortality rate and limited prediction and therapeutic options. In this study, for the first time, to our knowledge, we found that downregulation and/or blockade of T cell Ig and mucin domain protein 3 (Tim-3), a negative immune regulator, correlated with severity of sepsis, suggesting that Tim-3 plays important roles in maintaining the homeostasis of sepsis in both humans and a mouse model. Blockade and/or downregulation of Tim-3 led to increased macrophage activation, which contributed to the systemic inflammatory response in sepsis, whereas Tim-3 overexpression in macrophages significantly suppressed TLR-mediated proinflammatory cytokine production, indicating that Tim-3 is a negative regulator of TLR-mediated immune responses. Cross-talk between the Tim-3 and TLR4 pathways makes TLR4 an important contributor to Tim-3-mediated negative regulation of the innate immune response. Tim-3 signaling inhibited LPS-TLR4-mediated NF-κB activation by increasing PI3K-AKT phosphorylation and A20 activity. This negative regulatory role of Tim-3 reflects a new adaptive compensatory and protective mechanism in sepsis victims, a finding of potential importance for modulating innate responses in these patients.
Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
Xiaomei
X
Yang
Xingwei
X
Jiang
Guojiang
G
Chen
Yan
Y
Xiao
Shaoxia
S
Geng
Chunyan
C
Kang
Tingting
T
Zhou
Yurong
Y
Li
Xiaoqin
X
Guo
He
H
Xiao
Chunmei
C
Hou
Renxi
R
Wang
Zhou
Z
Lin
Xinying
X
Li
Jiannan
J
Feng
Yuanfang
Y
Ma
Beifen
B
Shen
Yan
Y
Li
Gencheng
G
Han
D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005786:Gene Expression Regulation; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D018805:Sepsis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D012720:Severity of Illness Index; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000276:immunology
D015415:Biomarkers; D016207:Cytokines; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt