T Cell Ig Mucin-3 Promotes Homeostasis of Sepsis by Negatively Regulating the TLR Response(1)
Sepsis is a life-threatening condition caused by different microorganisms that enter the bloodstream and trigger an excessive inflammatory response. TLRs are pattern recognition receptors that recognize conserved microbial molecules called pathogen-associated molecular pattern molecules. Activation of TLR4 represents an important triggering event in the development of infectious and inflammatory diseases. Bacterial LPS binds to myeloid differentiation protein 2 (MD2) in the MD2–TLR4 complex and triggers a signaling cascade causing secretion of MyD88 and TRIF-dependent proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6. T cell Ig and mucin domain protein 3 (Tim-3) was initially identified on terminally differentiated Th1, Th17, and Tc1 cells, and was thought to function directly in regulating T cell responses. The TLR system can be negatively regulated by Tim-3.
In a mouse sepsis model established by CLP, administration of anti–Tim-3 mAb decreased the survival rate and also increased levels of mRNAs coding for the proinflammatory cytokines IL-6, IL-1β, and HMGB1. As TLR4 and TLR2 are two important mediators of excessive inflammatory responses during polymicrobial sepsis, TLR4 and TLR2 mRNAs after Tim-3 blockade and found that both were increased. mRNA levels for the anti-inflammatory cytokine IL-10 were increased after Tim-3 blockade.
Tim-3 blockade did not significantly affect the survival rate for sepsis in TLR4 KO mice, showing that Tim-3 exerts its negative function by downregulating the LPS/TLR4 pathway. Levels of mRNAs for IL-1β, IL-10, IL-6, and HMGB1 in splenocytes were only slightly upregulated, compared with controls. Tim-3 is actively involved in maintaining the homeostasis of sepsis by inhibiting the TLR4 response.
In an LPS-induced endotoxinemia mouse model, Tim-3 blockade with anti–Tim-3 mAb again significantly enhanced expression of the proinflammatory cytokines IL-6 and IL-1β, the anti-inflammatory cytokine IL-10, and TLR4. These data further demonstrate a cross-talk between the TLR4 and Tim-3 pathways in the progression of inflammation and indicate that TLR4 is a critical target of Tim-3–mediated negative regulation.
The mechanisms by which Tim-3 negatively regulates the TLR response and promotes homeostasis of sepsis are summarized.
