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The detrimental effects of chronic lung inflammation on mental health are well recognized, however, underlying mechanisms are not known. Here, using a murine model of allergic asthma we report compromised fear extinction in mice with severe but not mild airway inflammation (AI); an effect abolished by anti-interleukin-17A (IL-17A) antibodies. Investigation of innate immune cells, microglia as-well-as transcriptomic signatures in the subfornical organ (SFO), a brain interoceptive node lacking a traditional blood-brain-barrier, revealed significant alterations in severe AI mice. IL-17 Receptor A (IL-17RA) was expressed in SFO microglia and upregulated in severe AI mice. Notably, ablation of microglial IL-17RA improved fear extinction in severe AI mice. Furthermore, we identified direct SFO projections to the infralimbic (IL) cortex, a key area regulating extinction. Importantly, chemogenetic inhibition of the SFO-IL circuit led to improved fear extinction in severe AI mice. Collectively, we report a unique body-to-brain interoceptive mechanism engaging the SFO and an SFO-to-IL circuit, through which airway inflammatory mediators compromise fear extinction. Beyond asthma, our findings are relevant to other pulmonary pathologies (e.g. bacterial pneumonia, ARDS, COVID-19) highlighting a risk for cortical dysfunction and fear pathologies such as PTSD.<\/jats:p>","DOI":"10.1101\/2025.07.16.664367","type":"posted-content","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T19:10:11Z","timestamp":1752865811000},"source":"Crossref","is-referenced-by-count":1,"title":["A novel interoceptive subfornical organ to infralimbic cortex circuit relays airway inflammation effects on fear extinction"],"prefix":"10.64898","author":[{"given":"Emily","family":"Allgire","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaclyn W.","family":"McAlees","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca A.","family":"Ahlbrand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Mancz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren L.","family":"Vollmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Winter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine M.J.","family":"McMurray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Maile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Sanders","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William G.","family":"Ryan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan-Hermann","family":"Pool","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igal","family":"Ifergan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric S.","family":"Wohleb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Davidson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert E.","family":"McCullumsmith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian P.","family":"Lewkowich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renu","family":"Sah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025072108450920000_2025.07.16.664367v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cpnec.2023.100186"},{"key":"2025072108450920000_2025.07.16.664367v1.2","doi-asserted-by":"publisher","DOI":"10.1007\/s11920-009-0034-9"},{"key":"2025072108450920000_2025.07.16.664367v1.3","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-017-5009-4"},{"key":"2025072108450920000_2025.07.16.664367v1.4","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/S2215-0366(21)00084-5","article-title":"6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records","volume":"8","year":"2021","journal-title":"Lancet Psychiatry"},{"key":"2025072108450920000_2025.07.16.664367v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2021.07.018"},{"key":"2025072108450920000_2025.07.16.664367v1.6","doi-asserted-by":"publisher","DOI":"10.1097\/00005053-200205000-00001"},{"key":"2025072108450920000_2025.07.16.664367v1.7","doi-asserted-by":"publisher","DOI":"10.5588\/ijtld.14.0170"},{"key":"2025072108450920000_2025.07.16.664367v1.8","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1016\/S0140-6736(21)01450-1","article-title":"Worldwide trends in the burden of asthma symptoms in school-aged children: Global Asthma Network Phase I cross-sectional study","volume":"398","year":"2021","journal-title":"Lancet Lond. 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