Interleukin-33-Dependent Accumulation of Regulatory T Cells Mediates Pulmonary Epithelial Regeneration During Acute Respiratory Distress Syndrome.

Wen Tan,Jianzhou Liu,Qi Miao,Xinpei Liu,Chaoji Zhang,Bohan Zhang

doi:10.3389/fimmu.2021.653803

Abstract

Acute respiratory distress syndrome (ARDS) triggered mostly by infection, is a syndrome that involves respiratory failure. ARDS induces strong local infiltration of regulatory T cells (Treg cells) in the lungs, and Treg cells were recently highlighted as being related to the repair of various tissue. However, at present, there is still a lack of adequate evidence showing the impact of Treg cells on pulmonary regeneration during ARDS. Here, we verified that Treg cells are strongly induced in ARDS mice and Treg depletion results in impaired lung repair. Moreover, Treg cells show high expression of ST2, a cellular receptor for the tissue alarmin IL-33, which is strongly upregulated in the lung during ARDS. In addition, we demonstrated that IL-33 signaling is crucial for Treg cell accumulation, and ST2-blocked mice show a decrease in the Treg cell population. Critically, transfer of exogenous IL-33 into Treg depleted mice restored Treg cells and facilitated lung regeneration by promoting alveolar type II cell (AEC2) recovery in ARDS, with elevated neutrophils infiltration and upregulated TGF-β1 release. These results emphasized the importance of IL-33 in accelerating the expansion of pulmonary Treg cells and promoting their activity to mediate pulmonary epithelial regeneration during ARDS in a TGF-β1-dependent manner.

Highlights

Acute respiratory distress syndrome (ARDS), which is triggered mostly by infection, has hallmarks that include expiratory dyspnea and progressive hypoxemia, and the pivotal precipitating events are activation of the inflammatory micro-environment and diffuse alveolar damage (DAD)
A process initiated by the proliferation and migration of endogenous progenitor alveolar type II cells (AEC2s), followed by their differentiation into alveolar type I cells (AEC1s) and restoration of epithelial barrier function, is still the focus of ongoing investigation
Male mice were randomly allocated into several groups as follows: sham group, LPS-12-h group (L12h), LPS-1-day group (L1), LPS-2-day group (L2), LPS-4-day group (L4), LPS-7-day group (L7), LPS-9-day group (L9), LPS-11-day group (L11), and LPS-14-day group (L14)

Summary

Introduction

Acute respiratory distress syndrome (ARDS), which is triggered mostly by infection, has hallmarks that include expiratory dyspnea and progressive hypoxemia, and the pivotal precipitating events are activation of the inflammatory micro-environment and diffuse alveolar damage (DAD). The lung immediately mounts a regenerative process orchestrated by intricate immune interaction. Epithelial repair, especially alveolar epithelial regeneration acts a significant part. A process initiated by the proliferation and migration of endogenous progenitor alveolar type II cells (AEC2s), followed by their differentiation into alveolar type I cells (AEC1s) and restoration of epithelial barrier function, is still the focus of ongoing investigation. Previous study suggested a critical contribution of Treg cells to pulmonary repair via cross-talk between the adaptive and innate immune systems [4, 5]. The upregulation of Treg cells was correlated with the induction of immune tolerance [6], and pivotal in restricting damage and coordinating the repair process

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Conclusion