锌指蛋白A20对Toll样受体信号途径的负反馈调控及其对机体的保护作用

Toll-like receptors (TLRs) recognize pathogens and initiate innate immune responses at the early stage of virus invasion, promoting the maturation and differentiation of immune cells, regulating immune respon-ses,and triggering inflammatory responses. Lipopolysaccharide (LPS) activates the TLR4 signaling pathways which result in the activation of NFκB and JNK/SAPK and the expression of large amounts of inflammatory fac-tors,leading to systemic inflammatory response and multiple organ failure. A20, a NFκB-dependant cytosolic protein, via a negative feedback loop blocks NFκB activation and participates in the regulation of inflammatory responses and the inhibition of apptosis;therefore, it provides protective effect on the body.     

锌指蛋白A20对Toll样受体信号途径的负反馈调控及其对机体的保护作用

Toll-like receptors (TLRs) recognize pathogens and initiate innate immune responses at the early stage of virus invasion, promoting the maturation and differentiation of immune cells, regulating immune respon-ses,and triggering inflammatory responses. Lipopolysaccharide (LPS) activates the TLR4 signaling pathways which result in the activation of NFκB and JNK/SAPK and the expression of large amounts of inflammatory fac-tors,leading to systemic inflammatory response and multiple organ failure. A20, a NFκB-dependant cytosolic protein, via a negative feedback loop blocks NFκB activation and participates in the regulation of inflammatory responses and the inhibition of apptosis;therefore, it provides protective effect on the body.     

锌指蛋白A20对Toll样受体信号途径的负反馈调控及其对机体的保护作用

Toll-like receptors (TLRs) recognize pathogens and initiate innate immune responses at the early stage of virus invasion, promoting the maturation and differentiation of immune cells, regulating immune respon-ses,and triggering inflammatory responses. Lipopolysaccharide (LPS) activates the TLR4 signaling pathways which result in the activation of NFκB and JNK/SAPK and the expression of large amounts of inflammatory fac-tors,leading to systemic inflammatory response and multiple organ failure. A20, a NFκB-dependant cytosolic protein, via a negative feedback loop blocks NFκB activation and participates in the regulation of inflammatory responses and the inhibition of apptosis;therefore, it provides protective effect on the body.     

锌指蛋白A20对Toll样受体信号途径的负反馈调控及其对机体的保护作用

Toll-like receptors (TLRs) recognize pathogens and initiate innate immune responses at the early stage of virus invasion, promoting the maturation and differentiation of immune cells, regulating immune respon-ses,and triggering inflammatory responses. Lipopolysaccharide (LPS) activates the TLR4 signaling pathways which result in the activation of NFκB and JNK/SAPK and the expression of large amounts of inflammatory fac-tors,leading to systemic inflammatory response and multiple organ failure. A20, a NFκB-dependant cytosolic protein, via a negative feedback loop blocks NFκB activation and participates in the regulation of inflammatory responses and the inhibition of apptosis;therefore, it provides protective effect on the body.     

锌指蛋白A20对Toll样受体信号途径的负反馈调控及其对机体的保护作用

Toll-like receptors (TLRs) recognize pathogens and initiate innate immune responses at the early stage of virus invasion, promoting the maturation and differentiation of immune cells, regulating immune respon-ses,and triggering inflammatory responses. Lipopolysaccharide (LPS) activates the TLR4 signaling pathways which result in the activation of NFκB and JNK/SAPK and the expression of large amounts of inflammatory fac-tors,leading to systemic inflammatory response and multiple organ failure. A20, a NFκB-dependant cytosolic protein, via a negative feedback loop blocks NFκB activation and participates in the regulation of inflammatory responses and the inhibition of apptosis;therefore, it provides protective effect on the body.     

锌指蛋白A20对Toll样受体信号途径的负反馈调控及其对机体的保护作用

Toll-like receptors (TLRs) recognize pathogens and initiate innate immune responses at the early stage of virus invasion, promoting the maturation and differentiation of immune cells, regulating immune respon-ses,and triggering inflammatory responses. Lipopolysaccharide (LPS) activates the TLR4 signaling pathways which result in the activation of NFκB and JNK/SAPK and the expression of large amounts of inflammatory fac-tors,leading to systemic inflammatory response and multiple organ failure. A20, a NFκB-dependant cytosolic protein, via a negative feedback loop blocks NFκB activation and participates in the regulation of inflammatory responses and the inhibition of apptosis;therefore, it provides protective effect on the body.     

锌指蛋白A20对Toll样受体信号途径的负反馈调控及其对机体的保护作用

Toll-like receptors (TLRs) recognize pathogens and initiate innate immune responses at the early stage of virus invasion, promoting the maturation and differentiation of immune cells, regulating immune respon-ses,and triggering inflammatory responses. Lipopolysaccharide (LPS) activates the TLR4 signaling pathways which result in the activation of NFκB and JNK/SAPK and the expression of large amounts of inflammatory fac-tors,leading to systemic inflammatory response and multiple organ failure. A20, a NFκB-dependant cytosolic protein, via a negative feedback loop blocks NFκB activation and participates in the regulation of inflammatory responses and the inhibition of apptosis;therefore, it provides protective effect on the body.     

锌指蛋白A20对Toll样受体信号途径的负反馈调控及其对机体的保护作用

Toll-like receptors (TLRs) recognize pathogens and initiate innate immune responses at the early stage of virus invasion, promoting the maturation and differentiation of immune cells, regulating immune respon-ses,and triggering inflammatory responses. Lipopolysaccharide (LPS) activates the TLR4 signaling pathways which result in the activation of NFκB and JNK/SAPK and the expression of large amounts of inflammatory fac-tors,leading to systemic inflammatory response and multiple organ failure. A20, a NFκB-dependant cytosolic protein, via a negative feedback loop blocks NFκB activation and participates in the regulation of inflammatory responses and the inhibition of apptosis;therefore, it provides protective effect on the body.     

锌指蛋白A20对Toll样受体信号途径的负反馈调控及其对机体的保护作用

Toll-like receptors (TLRs) recognize pathogens and initiate innate immune responses at the early stage of virus invasion, promoting the maturation and differentiation of immune cells, regulating immune respon-ses,and triggering inflammatory responses. Lipopolysaccharide (LPS) activates the TLR4 signaling pathways which result in the activation of NFκB and JNK/SAPK and the expression of large amounts of inflammatory fac-tors,leading to systemic inflammatory response and multiple organ failure. A20, a NFκB-dependant cytosolic protein, via a negative feedback loop blocks NFκB activation and participates in the regulation of inflammatory responses and the inhibition of apptosis;therefore, it provides protective effect on the body.     

Toll-dependent control mechanisms of CD4 T cell activation

Toll-like receptors (TLRs) detect microbial infection and play an essential role in the induction of innate and adaptive immune responses. The mechanisms of TLR-mediated control of adaptive immunity are not yet fully understood. Induction of dendritic cell (DC) maturation is essential for activation of naive T cells. Here, we demonstrate that TLR-induced DC maturation and migration to the lymph nodes, in the absence of TLR-induced inflammatory cytokines, are not sufficient for T cell activation in vivo. We show that transient depletion of regulatory T (Tr) cells recovers the primary CD4 T cells response in MyD88-deficient mice, demonstrating that a major mechanism of TLR-mediated activation of T cell responses is the blocking of suppression by regulatory T cells. In addition we show that a TLR-induced signal(s) is required for memory CD4 T cell differentiation, but not for activation of memory T cells.     

TLR activation enhances C5a-induced pro-inflammatory responses by negatively modulating the second C5a receptor, C5L2

TLR and complement activation ensures efficient clearance of infection. Previous studies documented synergism between TLRs and the receptor for the pro-inflammatory complement peptide C5a (C5aR/CD88), and regulation of TLR-induced pro-inflammatory responses by C5aR, suggesting crosstalk between TLRs and C5aR. However, it is unclear whether and how TLRs modulate C5a-induced pro-inflammatory responses. We demonstrate a marked positive modulatory effect of TLR activation on cell sensitivity to C5a in vitro and ex vivo and identify an underlying mechanistic target. Pre-exposure of PBMCs and whole blood to diverse TLR ligands or bacteria enhanced C5a-induced pro-inflammatory responses. This effect was not observed in TLR4 signalling-deficient mice. TLR-induced hypersensitivity to C5a did not result from C5aR upregulation or modulation of C5a-induced Ca(2+) mobilization. Rather, TLRs targeted another C5a receptor, C5L2 (acting as a negative modulator of C5aR), by reducing C5L2 activity. TLR-induced hypersensitivity to C5a was mimicked by blocking C5L2 and was not observed in C5L2KO mice. Furthermore, TLR activation inhibited C5L2 expression upon C5a stimulation. These findings identify a novel pathway of crosstalk within the innate immune system that amplifies innate host defense at the TLR-complement interface. Unravelling the mutually regulated activities of TLRs and complement may reveal new therapeutic avenues to control inflammation.     

Crosstalk among Jak-STAT, Toll-like receptor, and ITAM-dependent pathways in macrophage activation

Macrophage phenotype and activation are regulated by cytokines that use the Jak-STAT signaling pathway, microbial recognition receptors that include TLRs, and immunoreceptors that signal via ITAM motifs. The amplitude and qualitative nature of macrophage activation are determined by crosstalk among these signaling pathways. Basal ITAM signaling restrains macrophage responses to TLRs and other activating ligands, whereas strong ITAM signals synergize with the same ligands to activate cells strongly. Similarly, basal ITAM signaling augments IFN signaling and function of receptor activator of NF-kappaB, but extensive ITAM activation inhibits Jak-STAT signaling. Thus, intensity and duration of ITAM signaling determine whether ITAM-coupled receptors augment or attenuate TLR and Jak-STAT responses. IFN-gamma synergizes with TLRs in part by suppressing TLR-induced feedback inhibition, mediated by IL-10 and Stat3, by a mechanism that depends on glycogen synthase kinase (GSK)3 regulation of AP-1 and CREB. IFN-gamma suppresses TLR2 and TLR4 induction/activation of AP-1 by overlapping mechanisms that include regulation of MAPKs, GSK3-dependent suppression of DNA binding, and decreased Fos and Jun protein expression and stability. IFN-gamma suppression of TLR-induced activation of AP-1 and downstream target genes challenges current concepts about the inflammatory role of AP-1 proteins in macrophage activation and is consistent with a role for AP-1 in the generation of noninflammatory osteoclasts. Jak-STAT, TLR, and ITAM pathways are basally active in macrophages and strongly induced during innate responses. Thus, signal transduction crosstalk is regulated in a dynamic manner, which differs under homeostatic and pathologic conditions, and dysregulation of signal transduction crosstalk may contribute to pathogenesis of chronic inflammatory diseases.