SIRPαengagement regulates ILC2 effector function and alleviates airway hyperreactivity via modulating energy metabolism  

作　　者：Yoshihiro Sakano Kei Sakano Benjamin PHurrell Pedram Shafiei-Jahani Mohammad Hossein Kazemi Xin Li Stephen Shen Richard Barbers Omid Akbari 

机构地区：[1]Department of Molecular Microbiology and Immunology,Keck School of Medicine,University of Southern California,Los Angeles,CA,USA

出　　处：《Cellular & Molecular Immunology》2024年第10期1158-1174,共17页中国免疫学杂志（英文版）

基　　金：supported by R01 HL144790,R01 HL151493,R01 AI145813,R01 AI169687,R01 HL151769,R01 HL 159804 grant from the National Institutes of Health,Public Health Service(O.A.).Schematic diagrams(Figure 4E and Figure 6K)were designed with Biorender.com.

摘　　要：Group-2 innate lymphoid cells(ILC2)are part of a growing family of innate lymphocytes known for their crucial role in both the development and exacerbation of allergic asthma.The activation and function of ILC2s are regulated by various activating and inhibitory molecules,with their balance determining the severity of allergic responses.In this study,we aim to elucidate the critical role of the suppressor molecule signal regulatory protein alpha(SIRPα),which interacts with CD47,in controlling ILC2-mediated airway hyperreactivity(AHR).Our data indicate that activated ILC2s upregulate the expression of SIRPα,and the interaction between SIRPαand CD47 effectively suppresses both ILC2 proliferation and effector function.To evaluate the function of SIRPαin ILC2-mediated AHR,we combined multiple approaches including genetically modified mouse models and adoptive transfer experiments in murine models of allergen-induced AHR.Our findings suggest that the absence of SIRPαleads to the overactivation of ILC2s.Conversely,engagement of SIRPαwith CD47 reduces ILC2 cytokine production and effectively regulates ILC2-dependent AHR.Furthermore,the SIRPα-CD47 axis modulates mitochondrial metabolism through the JAK/STAT and ERK/MAPK signaling pathways,thereby regulating NF-κB activity and the production of type 2 cytokines.Additionally,our studies have revealed that SIRPαis inducible and expressed on human ILC2s,and administration of human CD47-Fc effectively suppresses the effector function and cytokine production.Moreover,administering human CD47-Fc to humanized ILC2 mice effectively alleviates AHR and lung inflammation.These findings highlight the promising therapeutic potential of targeting the SIRPα-CD47 axis in the treatment of ILC2-dependent allergic asthma.

关 键 词：SIRPa CD47 ILC2 AHR ASTHMA 

分 类 号：R392[医药卫生—免疫学]