biostudies-literatureZhang HNatural Science Foundation of ShanghaiNational Natural Science Foundation of ChinaShanghai Jiao Tong Universitye20211828https://www.ebi.ac.uk/biostudies/studies/S-EPMC8961293biostudies-literatureUnknown219(5)Alveolar macrophages (AMs) are specialized tissue-resident macrophages that orchestrate the immune response in allergic inflammation and asthma. However, what signals direct AMs to cross talk with other immune cells remains unclear. Here, we report that autocrine motility factor receptor (AMFR), an endoplasmic reticulum-resident E3 ubiquitin ligase, is upregulated in AMs of asthma and is critical for this condition. AMFR deficiency significantly decreased allergy-induced T helper 2 (Th2) and eosinophilic inflammation, with less granulocyte-macrophage colony-stimulating factor (GM-CSF) production in AMs. Mechanistically, following thymic stromal lymphopoietin (TSLP) stimulation, AMFR associated directly with cytokine-inducible SH2-containing protein (CIS), induced the ubiquitination of Lys4The Journal of experimental medicineAMFR drives allergic asthma development by promoting alveolar macrophage-derived GM-CSF production.PMC89612938217382119X16001000521ZR1432700817737418207385881973329Yang XXu LSun LWei RChen ZQian FZhang HJiang HLi MfalseAMFR drives allergic asthma development by promoting alveolar macrophage-derived GM-CSF production.Alveolar macrophages (AMs) are specialized tissue-resident macrophages that orchestrate the immune response in allergic inflammation and asthma. However, what signals direct AMs to cross talk with other immune cells remains unclear. Here, we report that autocrine motility factor receptor (AMFR), an endoplasmic reticulum-resident E3 ubiquitin ligase, is upregulated in AMs of asthma and is critical for this condition. AMFR deficiency significantly decreased allergy-induced T helper 2 (Th2) and eosinophilic inflammation, with less granulocyte-macrophage colony-stimulating factor (GM-CSF) production in AMs. Mechanistically, following thymic stromal lymphopoietin (TSLP) stimulation, AMFR associated directly with cytokine-inducible SH2-containing protein (CIS), induced the ubiquitination of Lys42022-01-01T00:00:00Z2022 May2026-05-03T10:56:56.009Z2025-04-05T13:44:32.19ZS-EPMC89612933533329610.1084/jem.20211828