[HTML][HTML] IL-33–mediated IL-13 secretion by ST2+ Tregs controls inflammation after lung injury

Q Liu, GK Dwyer, Y Zhao, H Li, LR Mathews… - JCI insight, 2019 - ncbi.nlm.nih.gov
Q Liu, GK Dwyer, Y Zhao, H Li, LR Mathews, AB Chakka, UR Chandran, JA Demetris…
JCI insight, 2019ncbi.nlm.nih.gov
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 …
Abstract
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 Ly6C hi 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 Tregs to secrete IL-13. Using Foxp3 Cre× Il4/Il13 fl/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 Ly6C hi monocytes. Our study identifies a 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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