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.

Differential Macrophage Response to Slow- and Fast-Growing Pathogenic Mycobacteria

“…In consequence, the important induction of IL-1 β secretion by fast-growing mycobacteria is consistent with their ROS production, since both mechanisms contribute to inflammasome activation. This has been suggested for the fast grower M. abscessus [62] and has been previously demonstrated only for the slow grower M. kansasii [52]. In contrast, M. celatum induced the lowest level of IL-1 β (even lower than that of M. tuberculosis ), which suggests that this may be another immune-evasion strategy.…”

Critical role for calcium mobilization in activation of the NLRP3 inflammasome

“…Previous studies relying mainly on 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA)-AM treatment or incubation in Ca 2+ -free media have made somewhat inconsistent conclusions regarding the role of Ca 2+ in NLRP3 inflammasome activation (28,(37)(38)(39). Given the pleitropic effects of BAPTA-AM on many cellular processes including LPS signaling (40), we wished to more carefully examine this issue by defining specific regulators of Ca 2+ mobilization.…”

Checks and Balances between Autophagy and Inflammasomes during Infection

“…In contrast, inflammasome activation and IL-1β secretion restricted growth by Mycobacterium kansasii in human macrophages [180]. Mycobacterium abscessus also activates NRLP3 in human macrophages via Syk kinase and the C-type lectin, Dectin-1 [181]. NLRP3 or ACS knockdown by RNA interference resulted in a significant reduction of IL-1β and a significant increase of viable M. abscessus in macrophages, suggesting that inflammasome activation is important in host defense with this pathogenic NTM.…”