IL-33-mediated IL-13 secretion by ST2+ Treg controls inflammation after lung injury

Liu Q, Dwyer GK, Zhao Y, Li H, Mathews LR, Chakka AB, Chandran UR, Demetris JA, Alcorn JF, Robinson KM, Ortiz LA, Pitt B, Thomson AW, Fan MH, BIlliar TR, Turnquist HR. IL-33-mediated IL-13 secretion by ST2+ Treg controls inflammation after lung injury. JCI Insight. 2019 Feb 19. pii: 123919. doi: 10.1172/jci.insight.123919. Epub ahead of print. PMID: 20779711.

Acute respiratory distress syndrome is an often fatal disease that develops after acute lung injury and trauma. How released tissue damage signals, or alarmins, orchestrate early inflammatory events is poorly understood. Herein we reveal that IL-33, an alarmin sequestered in the lung epithelium, is required to limit inflammation after injury due to an unappreciated capacity to mediate Foxp3+ Treg control of local cytokines and myeloid populations. Specifically, Il33-/- mice are more susceptible to lung damage-associated morbidity and mortality that is typified by augmented levels of the proinflammatory cytokines and Ly6Chi monocytes in the bronchoalveolar lavage fluid. Local delivery of IL-33 at the time of injury is protective, but requires the presence of Treg cells. IL-33 stimulates both mouse and human Treg to secrete IL-13. Using Foxp3Cre x Il4/Il13fl/fl mice, we show that Treg expression of IL-13 is required to prevent mortality after acute lung injury by controlling local levels of G-CSF, IL-6, and MCP-1 and inhibiting accumulation of Ly6Chi monocytes. Our study identifies a new regulatory mechanism involving IL-33 and Treg secretion of IL-13 in response to tissue damage that is instrumental in limiting local inflammatory responses and may shape the myeloid compartment after lung injury.

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2019
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Liu Q, Dwyer GK, Zhao Y, Li H, Mathews LR, Chakka AB, Chandran UR, Demetris JA, Alcorn JF, Robinson KM, Ortiz LA, Pitt B, Thomson AW, Fan MH, BIlliar TR, Turnquist HR
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