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

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.

• Authors: Rendong Fang, Ryosuke Uchiyama, Shunsuke Sakai, Hideki Hara, Hiroko Tsutsui, Takashi Suda, Masao Mitsuyama, Ikuo Kawamura, Kohsuke Tsuchiya
• Journal: Mucosal immunology (Mucosal Immunol) Vol. 12 Issue 5 Pg. 1092-1103 (09 2019) ISSN: 1935-3456 [Electronic] United States
• PMID: 31278375 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CARD Signaling Adaptor Proteins
• Cytokines
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Proto-Oncogene Proteins c-ets
• Pycard protein, mouse
• STAT6 Transcription Factor
• Spdef protein, mouse
• Casp4 protein, mouse
• Caspases, Initiator
• Caspase 1

Topics

• Animals
• CARD Signaling Adaptor Proteins (genetics, metabolism)
• Caspase 1 (metabolism)
• Caspases, Initiator (metabolism)
• Cytokines (metabolism)
• Flow Cytometry
• Genes, Reporter
• Homeostasis
• Immunity, Innate
• Immunity, Mucosal
• Inflammasomes (metabolism)
• Mice
• Mice, Knockout
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics, metabolism)
• Neutrophil Infiltration
• Neutrophils (immunology, metabolism)
• Pneumococcal Infections (immunology, microbiology)
• Proto-Oncogene Proteins c-ets (genetics, metabolism)
• Respiratory Mucosa (immunology, metabolism)
• STAT6 Transcription Factor (genetics, metabolism)
• Streptococcus pneumoniae (immunology)