A vagal-to-sympathetic reflex controls lung vascular leak

Dynamic regulation of the vascular barrier is required for an effective inflammatory response, allowing delivery of plasma proteins and immune cells to sites of insult. Although normally protective, sustained leak becomes costly in organs like the lung, where swelling stiffens tissue and impairs breathing, yet many upstream regulators remain unidentified. Using a chemogenetic screen of vagal afferent subtypes, we identify a neural reflex that drives lung vascular leak. The reflex originates in an orphan population of neurons expressing Cysltr2 that innervates alveolar capillary beds and senses both mechanical and inflammatory stimuli, fitting classic definitions of pulmonary "J" receptors, an afferent subtype described anatomically since the 1950s whose function has remained speculative. Activating CYSLTR2 neurons increases lung vascular leak within minutes and causes perivascular edema and respiratory dysfunction, whereas silencing them during inhaled allergen challenge reduces leak and improves lung mechanics. Rather than acting locally through antidromic peptide release, this reflex engages brainstem relays and sympathetic efferents to broadcast its effects throughout lung vasculature. Vagal control of the vascular barrier thus forms an axis of organ defense that can go awry in disease, revealing new ways to regulate organ fluid balance upstream of the endothelium.