Journal
IMMUNOLOGY AND CELL BIOLOGY
Volume 90, Issue 6, Pages 601-610Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/icb.2011.72
Keywords
Dectin-1; inflammasome; innate immunity; Mycobacterium abscessus; NLRP3
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Funding
- National Research Foundation of Korea (NRF)
- Korea government (MEST) through the Infection Signaling Network Research Center at Chungnam National University [2011-0006228]
- National Research Foundation of Korea [전06A1115, 2007-0055006] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Numerous atypical mycobacteria, including Mycobacterium abscessus (Mabc), cause nontuberculous mycobacterial infections, which present a serious public health threat. Inflammasome activation is involved in host defense and the pathogenesis of autoimmune diseases. However, inflammasome activation has not been widely characterized in human macrophages infected with atypical mycobacteria. Here, we demonstrate that Mabc robustly activates the nucleotide binding and oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome via dectin-1/Syk-dependent signaling and the cytoplasmic scaffold protein p62/SQSTM1 (p62) in human macrophages. Both dectin-1 and Toll-like receptor 2 (TLR2) were required for Mabc-induced mRNA expression of pro-interleukin (IL)-1 beta, cathelicidin human cationic antimicrobial protein-18/LL-37 and beta-defensin 4 (DEFB4). Dectin-1-dependent Syk signaling, but not that of MyD88, led to the activation of caspase-1 and secretion of IL-1 beta through the activation of an NLRP3/apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) inflammasome. Additionally, potassium efflux was required for Mabc-induced NLRP3/ASC inflammasome activation. Furthermore, Mabc-induced p62 expression was critically involved in NLRP3 inflammasome activation in human macrophages. Finally, NLRP3/ASC was critical for the inflammasome in antimicrobial responses to Mabc infection. Taken together, these data demonstrate the induction mechanism of the NLRP3/ASC inflammasome and its role in innate immunity to Mabc infection. Immunology and Cell Biology (2012) 90, 601-610; doi:10.1038/icb.2011.72; published online 30 August 2011
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