查看更多>>摘要：The innate immune responses,including inflammasome activation,are paramount for host defense against pathogen infection.In contrast to canonical and noncanonical inflammasome activation,in this study,heat-killed gram-negative bacteria(HK bacteria)were identified as single-step stimulators of the NLRP3 inflammasome in human monocytes,and they caused a moderate amount of IL-1 β to be released from cells.Time course experiments showed that this alternative inflammasome response was finished within a few hours.Further analysis showed that the intrinsically limited NLRP3 inflammasome activation response was due to the negative regulation of caspase-8 by the short isoform of cFLIP(cFLIPs),which was activated by NF-κB.In contrast,overexpressed cFLIPs,but not overexpressed cFLIPL,inhibited the activation of caspase-8 and the release of IL-1 β in response to HK bacteria infection in human monocytes.Furthermore,we demonstrated that TAK1 activity mediated the expression of cFLIPs and was upstream and essential for the caspase-8 cleavage induced by HK bacteria in human monocytes.The functional specificity of cFLIPs and TAK1 revealed unique responses of human monocytes to a noninvasive pathogen,providing novel insights into an alternative regulatory pathway of NLRP3 inflammasome activation.
查看更多>>摘要：Although DNA mutation drives stem cell aging,how mutation-accumulated stem cells obtain clonal advantage during aging remains poorly understood.Here,using a mouse model of irradiation-induced premature aging and middle-aged mice,we show that DNA mutation accumulation in hematopoietic stem cells(HSCs)during aging upregulates their surface expression of major histocompatibility complex class II(MHCII).MHCII upregulation increases the chance for recognition by bone marrow(BM)-resident regulatory T cells(Tregs),resulting in their clonal expansion and accumulation in the HSC niche.On the basis of the establishment of connexin 43(Cx43)-mediated gap junctions,BM Tregs transfer cyclic adenosine monophosphate(cAMP)to aged HSCs to diminish apoptotic priming and promote their survival via activation of protein kinase A(PKA)signaling.Importantly,targeting the HSC-Treg interaction or depleting Tregs effectively prevents the premature/physiological aging of HSCs.These findings show that aged HSCs use an active self-protective mechanism by entrapping local Tregs to construct a prosurvival niche and obtain a clonal advantage.
查看更多>>摘要：SEL1 L-mediated endoplasmic reticulum-associated degradation(ERAD)plays critical roles in controlling protein homeostasis by degrading misfolded or terminal unfolded proteins.However,it remains unclear how SEL1L regulates peripheral T-cell survival and homeostasis.Herein,we found that SEL1L deficiency led to a greatly reduced frequency and number of mature T cells,which was further validated by adoptive transfer experiments or bone marrow chimera experiments,accompanied by the induction of multiple forms of cell death.Furthermore,SEL1L deficiency selectively disrupted naïve CD8+T-cell homeostasis,as indicated by the severe loss of the naïve T-cell subset but an increase in the memory T-cell subset.We also found that SEL1L deficiency fueled mTORC1/c-MYC activation and induced a metabolic shift,which was largely attributable to enhanced expression of the IL-15 receptor α and β chains.Mechanistically,single-cell transcriptomic profiling and biochemical analyses further revealed that Sel1I-/-CD8+T cells harbored excessive ER stress,particularly aberrant activation of the PERK-ATF4-CHOP-Bim pathway,which was alleviated by supplementing IL-7 or IL-15.Importantly,PERK inhibition greatly resolved the survival defects of Sel1I-/-CD8+T cells.In addition,IRE1α deficiency decreased mTORC1 signaling in Sel1 I-/-naïve CD8+T cells by downregulating the IL-15 receptor αchain.Altogether,these observations suggest that the ERAD adaptor molecule SEL1L acts as an important checkpoint for preserving the survival and homeostasis of peripheral T cells by regulating the PERK signaling cascade and IL-15 receptor-mediated mTORC1 axis.
万方数据