Resident alveolar macrophageâ derived vesicular SOCS3 dampens allergic airway inflammation

Resident alveolar macrophages (AMs) suppress allergic inflammation in murine asthma models. Previously we reported that resident AMs can blunt inflammatory signaling in alveolar epithelial cells (ECs) by transcellular delivery of suppressor of cytokine signaling 3 (SOCS3) within extracellular vesicles (EVs). Here we examined the role of vesicular SOCS3 secretion as a mechanism by which AMs restrain allergic inflammatory responses in airway ECs. Bronchoalveolar lavage fluid (BALF) levels of SOCS3 were reduced in asthmatics and in allergenâ challenged mice. Ex vivo SOCS3 secretion was reduced in AMs from challenged mice and this defect was mimicked by exposing normal AMs to cytokines associated with allergic inflammation. Both AMâ derived EVs and synthetic SOCS3 liposomes inhibited the activation of STAT3 and STAT6 as well as cytokine gene expression in ECs challenged with ILâ 4/ILâ 13 and house dust mite (HDM) extract. This suppressive effect of EVs was lost when they were obtained from AMs exposed to allergic inflammationâ associated cytokines. Finally, inflammatory cell recruitment and cytokine generation in the lungs of OVAâ challenged mice were attenuated by intrapulmonary pretreatment with SOCS3 liposomes. Overall, AM secretion of SOCS3 within EVs serves as a brake on airway EC responses during allergic inflammation, but is impaired in asthma. Synthetic liposomes encapsulating SOCS3 can rescue this defect and may serve as a framework for novel therapeutic approaches targeting airway inflammation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/1/fsb220322-sup-0001-FigS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/2/fsb220322.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/3/fsb220322_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/4/fsb220322-sup-0005-TableS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/5/fsb220322-sup-0003-FigS3.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/6/fsb220322-sup-0004-FigS4.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154378/7/fsb220322-sup-0002-FigS2.pd