ASC and NLRP3 maintain innate immune homeostasis in the airway through an inflammasome-independent mechanism

Rendong Fang,Ryosuke Uchiyama,Shunsuke Sakai,Hideki Hara,Kohsuke Tsuchiya,Takashi Suda,Hiroko Tsutsui,Ikuo Kawamura,Masao Mitsuyama

doi:10.1038/s41385-019-0181-1

Abstract

It is widely accepted that inflammasomes protect the host from microbial pathogens by inducing inflammatory responses through caspase-1 activation. Here, we show that the inflammasome components ASC and NLRP3 are required for resistance to pneumococcal pneumonia, whereas caspase-1 and caspase-11 are dispensable. In the lung of S. pneumoniae-infected mice, ASC and NLRP3, but not caspase-1/11, were required for optimal expression of several mucosal innate immune proteins. Among them, TFF2 and intelectin-1 appeared to be protective against pneumococcal pneumonia. During infection, ASC and NLRP3 maintained the expression of the transcription factor SPDEF, which can facilitate the expression of the mucosal defense factor genes. Moreover, activation of STAT6, a key regulator of Spdef expression, depended on ASC and NLRP3. Overexpression of these inflammasome proteins sustained STAT6 phosphorylation induced by type 2 cytokines. Collectively, this study suggests that ASC and NLRP3 promote airway mucosal innate immunity by an inflammasome-independent mechanism involving the STAT6-SPDEF pathway.

Highlights

The airway surface is continuously exposed to microbes and foreign particles that are inhaled into the respiratory tract.[1]
These results suggest that ASC and NLRP3 protect the host from pneumococcal pneumonia in an inflammasome-independent manner
These results suggest that ASC and NLRP3 positively regulate the expression of SPDEF during S. pneumoniae infection, thereby maintaining the expression of SPDEF-regulated airway defense factors

Summary

Introduction

The airway surface is continuously exposed to microbes and foreign particles that are inhaled into the respiratory tract.[1] The airway epithelium forms a protective mucosal barrier between the external and internal environments. Airway epithelial cells, including ciliated and secretory cells, play a key role in the removal of inhaled microbes and particles through mucociliary clearance. Type II alveolar epithelial cells secrete surfactant proteins (SPs) that have protective effects against bacterial pathogens. The airway epithelium is usually active to maintain an effective mucosal barrier, thereby protecting the host from microbial colonization and infections. PLY plays a critical role in the pathogenicity of S. pneumoniae by disrupting tissue barriers, suppressing ciliary beating on epithelial cells, and inhibiting bactericidal activity of neutrophils.[3,4]

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