Sensing and signaling of immunogenic extracellular RNAs restrain group 2 innate lymphoid cell-driven acute lung inflammation and airway hyperresponsiveness

Li She; Hamad H Alanazi; Liping Yan; Edward G Brooks; Peter H Dube; Yan Xiang; Fushun Zhang; Yilun Sun; Yong Liu; Xin Zhang; Xiao-Dong Li

doi:10.1371/journal.pone.0236744

Sensing and signaling of immunogenic extracellular RNAs restrain group 2 innate lymphoid cell-driven acute lung inflammation and airway hyperresponsiveness

PLoS One. 2020 Jul 30;15(7):e0236744. doi: 10.1371/journal.pone.0236744. eCollection 2020.

Authors

Li She^{1

2}, Hamad H Alanazi¹, Liping Yan¹, Edward G Brooks³, Peter H Dube¹, Yan Xiang¹, Fushun Zhang¹, Yilun Sun¹, Yong Liu², Xin Zhang², Xiao-Dong Li¹

Affiliations

¹ Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States of America.
² Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.
³ Division of Immunology and Infectious Disease, Long School of Medicine, University of Texas Health San Antonio, San Antonio, TX, United States of America.

Abstract

Repeated exposures to environmental allergens in susceptible individuals drive the development of type 2 inflammatory conditions such as asthma, which have been traditionally considered to be mainly mediated by Th2 cells. However, emerging evidence suggest that a new innate cell type, group 2 innate lymphoid cells (ILC2), plays a central role in initiating and amplifying a type 2 response, even in the absence of adaptive immunity. At present, the regulatory mechanisms for controlling ILC2 activation remain poorly understood. Here we report that respiratory delivery of immunogenic extracellular RNA (exRNAs) derived from RNA- and DNA-virus infected cells, was able to activate a protective response against acute type 2 lung immunopathology and airway hyperresponsiveness (AHR) induced by IL-33 and a fungal allergen, A. flavus, in mice. Mechanistically, we found that the innate immune responses triggered by exRNAs had a potent suppressive effect in vivo on the proliferation and function of ILC2 without the involvement of adaptive immunity. We further provided the loss-of-function genetic evidence that the TLR3- and MAVS-mediated signaling axis is essential for the inhibitory effects of exRNAs in mouse lungs. Thus, our results indicate that the host detection of extracellular immunostimulatory RNAs generated during respiratory viral infections have an important function in the regulation of ILC2-driven acute lung inflammation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptive Immunity
Adaptor Proteins, Signal Transducing / physiology
Adaptor Proteins, Vesicular Transport / physiology
Allergens / immunology
Allergens / metabolism
Animals
Cytokines / metabolism
Extracellular Traps / immunology*
Extracellular Traps / metabolism
Immunity, Innate / immunology*
Interleukin-33 / immunology
Interleukin-33 / metabolism
Lymphocytes / immunology*
Lymphocytes / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Pneumonia / immunology*
Pneumonia / metabolism
Pneumonia / pathology
RNA / immunology*
RNA / metabolism
Respiratory Hypersensitivity / immunology*
Respiratory Hypersensitivity / metabolism
Respiratory Hypersensitivity / pathology
Signal Transduction
Th2 Cells / immunology
Th2 Cells / metabolism
Toll-Like Receptor 3 / physiology

Substances

Adaptor Proteins, Signal Transducing
Adaptor Proteins, Vesicular Transport
Allergens
Cytokines
IPS-1 protein, mouse
Interleukin-33
TICAM-1 protein, mouse
TLR3 protein, mouse
Toll-Like Receptor 3
RNA

Grants and funding

LS is supported by the China Scholarship Council and Hunan Provincial Innovation Foundation for Postgraduate (CX201713068). HHA is supported by the Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka, Saudi Arabia. X.-D.L. is supported by the UT Health San Antonio School of Medicine Startup Fund and the Max and Minnei Voelcker Fund.