title: Mycobacterium abscessus activates the NLRP3 inflammasome via Dectin-1-Syk and p62/SQSTM1.
abstract: 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)-1β, cathelicidin human cationic antimicrobial protein-18/LL-37 and β-defensin 4 (DEFB4). Dectin-1-dependent Syk signaling, but not that of MyD88, led to the activation of caspase-1 and secretion of IL-1β 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.
authors.affiliation: Department of Microbiology, Chungnam National University School of Medicine, Daejeon, Korea.
authors.forename: Hye-Mi
authors.initials: HM
authors.lastname: Lee
authors.forename: Jae-Min
authors.initials: JM
authors.lastname: Yuk
authors.forename: Ki-Hye
authors.initials: KH
authors.lastname: Kim
authors.forename: Jichan
authors.initials: J
authors.lastname: Jang
authors.forename: Gun
authors.initials: G
authors.lastname: Kang
authors.forename: Jin Bong
authors.initials: JB
authors.lastname: Park
authors.forename: Ji-Woong
authors.initials: JW
authors.lastname: Son
authors.forename: Eun-Kyeong
authors.initials: EK
authors.lastname: Jo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D023181:Antimicrobial Cationic Peptides; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D054804:Cathelicidins / Q000096:biosynthesis; D002460:Cell Line; D006801:Humans; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D037181:Lectins, C-Type / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D009165:Mycobacterium Infections, Nontuberculous / Q000276:immunology; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009170:Nontuberculous Mycobacteria / Q000276:immunology*; D011188:Potassium / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction; D000072377:Syk Kinase; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D023083:beta-Defensins / Q000096:biosynthesis; D000099181:Dectin-1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D023181:Antimicrobial Cationic Peptides; D002352:Carrier Proteins; D020170:Caspase 1; D054804:Cathelicidins; D058847:Inflammasomes; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011188:Potassium; D011505:Protein-Tyrosine Kinases; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; D000072377:Syk Kinase; D051195:Toll-Like Receptor 2; D023083:beta-Defensins; C546929:CLEC7A protein, human; D000099181:Dectin-1; C106641:DEFB4A protein, human; C507779:MYD88 protein, human; C453881:NLRP3 protein, human; C099718:SQSTM1 protein, human; C000606896:SYK protein, human