IRF8 Regulates Transcription of Naips for NLRC4 Inflammasome Activation

Rajendra Karki, Ein Lee, David Place, Parimal Samir, Jayadev Mavuluri, Bhesh Raj Sharma, Arjun Balakrishnan, R. K.Subbarao Malireddi, Rechel Geiger, Qifan Zhu, Geoffrey Neale, Thirumala Devi Kanneganti

Research output: Contribution to journalArticlepeer-review

129 Scopus citations

Abstract

Inflammasome activation is critical for host defenses against various microbial infections. Activation of the NLRC4 inflammasome requires detection of flagellin or type III secretion system (T3SS) components by NLR family apoptosis inhibitory proteins (NAIPs); yet how this pathway is regulated is unknown. Here, we found that interferon regulatory factor 8 (IRF8) is required for optimal activation of the NLRC4 inflammasome in bone-marrow-derived macrophages infected with Salmonella Typhimurium, Burkholderia thailandensis, or Pseudomonas aeruginosa but is dispensable for activation of the canonical and non-canonical NLRP3, AIM2, and Pyrin inflammasomes. IRF8 governs the transcription of Naips to allow detection of flagellin or T3SS proteins to mediate NLRC4 inflammasome activation. Furthermore, we found that IRF8 confers protection against bacterial infection in vivo, owing to its role in inflammasome-dependent cytokine production and pyroptosis. Altogether, our findings suggest that IRF8 is a critical regulator of NAIPs and NLRC4 inflammasome activation for defense against bacterial infection. Optimal activation of NLRC4 inflammasome in response to pathogenic bacteria is dependent on IRF8.

Original languageEnglish (US)
Pages (from-to)920-933.e13
JournalCell
Volume173
Issue number4
DOIs
StatePublished - May 3 2018
Externally publishedYes

Keywords

  • Burkholderia
  • ICSBP
  • IRF8
  • NAIP
  • NLR
  • NLRC4
  • PU.1
  • Salmonella
  • caspase-1
  • inflammasome

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

Fingerprint

Dive into the research topics of 'IRF8 Regulates Transcription of Naips for NLRC4 Inflammasome Activation'. Together they form a unique fingerprint.

Cite this