{"doi":"10.1101/2021.08.06.455421","title":"SIRPα sequesters SHP-2 to promote IL-4/13 signaling and alternative activation of macrophages","abstract":"Abstract The Th2 cytokines IL-4 and IL-13 through activation of their shared receptor IL-4Rα direct macrophage alternative activation to promote immunosuppression and wound healing. However, the mechanisms that control macrophage responses to IL-4/13 are not fully understood. Apart from driving JAK-STAT and PI3K-Akt pathways to polarize macrophages toward the alternative phenotype, the activated IL-4/13 receptors recruit negative regulators SHP-1 and SHP-2, which dephosphorylate IL-4Rα and decrease its signaling. Here we report that SIRPα spatially restricts SHP-2 and, by such, promotes IL-4/13 signaling and macrophage alternative activation. SIRPα executes this regulation via its cytoplasmic ITIMs/ITSMs that undergo phosphorylation by IL-4/13-induced, Src kinase-activated Bruton’s tyrosine kinase (Btk), resulting in recruitment of SHP-2 and preclusion of SHP-2 from binding to and inhibiting IL-4/13 receptors. Despite that this regulation occurs independent of CD47, extracellular CD47 ligation of SIRPα facilitates its cytoplasmic phosphorylation and SHP-2 sequestration, leading to stronger IL-4/13 signaling and enhanced macrophage expression of IL-10, TGFβ, CD206, arginase-1, etc. Conversely, deficiency of SIRPα allows SHP-2 to freely bind to γC or IL-13Rα1 and through which dephosphorylate IL-4Rα, dampening its signaling. Consistent with these findings, impaired wound healing in Sirpα −/− mice under experimental colitis correlated with a deficit of immunosuppressive macrophages in the colon, a condition that was corrected by transfusion of ex vivo-produced SIRPα high alternatively activated macrophages.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":226148,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9487,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":637292,"name":"Koby Kidder","orcid":null,"position":1,"is_corresponding":false},{"id":636007,"name":"Zhen Bian","orcid":"0000-0003-3409-9240","position":2,"is_corresponding":false},{"id":829146,"name":"Samantha Kuon Ting Chiang","orcid":"0000-0001-6770-0536","position":3,"is_corresponding":false},{"id":829147,"name":"Corbett Ouellette","orcid":"0000-0002-6862-0252","position":4,"is_corresponding":false},{"id":246499,"name":"Yuan Liu","orcid":"0000-0003-0535-0600","position":5,"is_corresponding":false},{"id":636008,"name":"Lei Shi","orcid":"0000-0002-6631-6732","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-18T23:54:34.185847Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}