查看更多>>摘要：Chemokines are an indispensable component of our immune system through the regulation of directional migration and activation of leukocytes.CXCL8 is the most potent human neutrophil-attracting chemokine and plays crucial roles in the response to infection and tissue injury.CXCL8 activity inherently depends on interaction with the human CXC chemokine receptors CXCR1 and CXCR2,the atypical chemokine receptor ACKR1,and glycosaminoglycans.Furthermore,(hetero)dimerization and tight regulation of transcription and translation,as well as post-translational modifications further fine-tune the spatial and temporal activity of CXCL8 in the context of inflammatory diseases and cancer.The CXCL8 interaction with receptors and glycosaminoglycans is therefore a promising target for therapy,as illustrated by multiple ongoing clinical trials.CXCL8-mediated neutrophil mobilization to blood is directly opposed by CXCL12,which retains leukocytes in bone marrow.CXCL12 is primarily a homeostatic chemokine that induces migration and activation of hematopoietic progenitor cells,endothelial cells,and several leukocytes through interaction with CXCR4,ACKR1,and ACKR3.Thereby,it is an essential player in the regulation of embryogenesis,hematopoiesis,and angiogenesis.However,CXCL12 can also exert inflammatory functions,as illustrated by its pivotal role in a growing list of pathologies and its synergy with CXCL8 and other chemokines to induce leukocyte chemotaxis.Here,we review the plethora of information on the CXCL8 structure,interaction with receptors and glycosaminoglycans,different levels of activity regulation,role in homeostasis and disease,and therapeutic prospects.Finally,we discuss recent research on CXCL12 biochemistry and biology and its role in pathology and pharmacology.
查看更多>>摘要：The balance between inflammatory T helper type 17(Th17)and immunosuppressive regulatory T(Treg)cells is critical for maintaining immune homeostasis in the human body and is tightly regulated under healthy conditions.An increasing number of studies have reported that deubiquitinases(DUBs)play a vital role in regulating Th17-and Treg-cell differentiation.However,the biological functions of only a small fraction of DUBs in Th17-and Treg-cell differentiation are well defined.In this study,we identified ubiquitin-specific peptidase 1(USP1)as a vital regulator of CD4+ T-cell differentiation.USP1 promoted Th17-cell differentiation but attenuated Treg-cell differentiation,thereby promoting the development of inflammatory diseases.Mechanistically,USP1 in CD4+ T cells enhanced the activity of RORγt but promoted the proteasomal degradation of Foxp3 through deubiquitination and stabilization of TAZ in vitro and in vivo.Notably,ML323,a specific inhibitor of the USP1/UAF1 deubiquitinase complex,inhibited Th17-cell differentiation and promoted Treg-cell differentiation in vitro and in vivo,indicating that ML323 might be a promising candidate for the treatment of diseases associated with an imbalance between Th17 and Treg cells.Our study highlights the critical role of USP1 in regulating adaptive immune responses and suggests that USP1 might be a drug target for the treatment of diseases associated with an imbalance between Th17 and Treg cells.
查看更多>>摘要：The NLRP3 inflammasome plays an essential role in resistance to bacterial infection.The nervous system secretes multiple neuropeptides affecting the nervous system as well as immune cells.The precise impact of the neuropeptide CGRP on NLRP3 inflammasome activation is still unclear.Here,we show that CGRP negatively regulates the antibacterial process of host cells.CGRP prevents NLRP3 inflammasome activation and reduces mature IL-1β secretion.Following NLRP3 inflammasome stimulation that triggers endosome leakage,CGRP internalized to endosomal compartments is released into the cell cytosol.Cytosolic CGRP binds directly to NLRP3 and dismantles the NLRP3-NEK7 complex,which is crucial for NLRP3 inflammasome activation.CGRP administration exacerbates bacterial infection,while the treatment with a CGRP antagonist has the opposite effect.Our study uncovers a unique role of CGRP in inhibiting inflammasome activation during infections,which might shed new light on antibacterial therapies in the future.
查看更多>>摘要：Upon recognition of foreign antigens,naïve B cells undergo rapid activation,growth,and proliferation.How B-cell growth and proliferation are coupled with activation remains poorly understood.Combining CRISPR/Cas9-mediated functional analysis and mouse genetics approaches,we found that Dhx33,an activation-induced RNA helicase,plays a critical role in coupling B-cell activation with growth and proliferation.Mutant mice with B-cell-specific deletion of Dhx33 exhibited impaired B-cell development,germinal center reactions,plasma cell differentiation,and antibody production.Dhx33-deficient B cells appeared normal in the steady state and early stage of activation but were retarded in growth and proliferation.Mechanistically,Dhx33 played an indispensable role in activation-induced upregulation of ribosomal DNA(rDNA)transcription.In the absence of Dhx33,activated B cells were compromised in their ability to ramp up 47S ribosomal RNA(rRNA)production and ribosome biogenesis,resulting in nucleolar stress,p53 accumulation,and cellular death.Our findings demonstrate an essential role for Dhx33 in coupling B-cell activation with growth and proliferation and suggest that Dhx33 inhibition is a potential therapy for lymphoma and antibody-mediated autoimmune diseases.
查看更多>>摘要：Psoriasis is a common chronic inflammatory skin disease characterized by inflammatory cell infiltration and epidermal hyperplasia.However,the regulatory complexity of cytokine and cellular networks still needs to be investigated.Here,we show that the expression of FXYD3,a member of the FXYD domain-containing regulators of Na+/K+ ATPases family,is significantly increased in the lesional skin of psoriasis patients and mice with imiquimod(IMQ)-induced psoriasis.IL-17A,a cytokine important for the development of psoriatic lesions,contributes to FXYD3 expression in human primary keratinocytes.FXYD3 deletion in keratinocytes attenuated the psoriasis-like phenotype and inflammation in an IMQ-induced psoriasis model.Importantly,FXYD3 promotes the formation of the IL-17R-ACT1 complex by competing with IL-17R for binding to TRAF3 and then enhances IL-17A signaling in keratinocytes.This promotes the activation of the NF-κB and MAPK signaling pathways and leads to the expression of proinflammatory factors.Our results clarify the mechanism by which FXYD3 serves as a mediator of IL-17A signaling in keratinocytes to form a positive regulatory loop to promote psoriasis exacerbation.Targeting FXYD3 may serve as a potential therapeutic approach in the treatment of psoriasis.
万方数据