AIM2 inflammasome mediates Arsenic-induced secretion of IL-1 β and IL-18

Abstract

Chronic sterile inflammation has been implicated in the pathogenesis of many cancers, including skin cancer. Chronic arsenic exposure is closely associated with the development of skin cancer. However, there is a lack of understanding how arsenic induces chronic inflammation in the skin. Interleukin-1 family cytokines play a central role in regulating immune and inflammatory response. IL-1α, IL-1β and IL-18 are three pro-inflammatory cytokines in IL-1 family. Their secretion, especially the secretion of IL-1β and IL-18, is regulated by inflammasomes which are multi-protein complexes containing sensor proteins, adaptor protein and caspase-1. The data from current study show sub-chronic arsenic exposure activates AIM2 inflammasome which in turn activates caspase-1 and enhances the secretion of IL-1β and IL-18 in HaCaT cells and the skin of BALB/c mice. In addition, arsenic-promoted activation of AIM2 inflammasome and increase of IL-1β/IL-18 production are inhibited by PKR inhibitor in HaCaT cells or in the skin of PKR mutant mice, indicating a potential role of PKR in arsenic-induced sterile inflammation.

Polymorphism of nucleotide binding domain-like receptor protein 3 (NLRP3) increases susceptibility of total urinary arsenic to renal cell carcinoma

“…Furthermore, the NLRP3 rs1539019 C allele additively and multiplicatively interacted significantly with the total urinary arsenic concentration in the increased risk of RCC. The relationships identified in this study may result from the effect of arsenic on NLRP3 inflammasome activation, which alters caspase-1 and IL-1β levels 11 and the risk of developing RCC. Perhaps, NLRP3 rs1539019 affects the gene expression or linkage disequilibrium of other functional gene polymorphisms, which enhances the risk of RCC.…”

“…One study has shown that arsenic trioxide (As 2 O 3 ) could induce nonalcoholic steatohepatitis, increase autophagy, NLRP3 inflammasome activation, and lipid accumulation, which leads to lipid-related gene dysregulation 14 . Another study demonstrated that arsenic enhanced the AIM2 inflammasome activation to increase IL-1 β/ IL-18 production 11 . In contrast, Ahn et al 15 demonstrated that arsenic could inhibit the activation of the NLRP3 inflammasome in macrophages in response to lipopolysaccharide treatment, which attenuated the elevation of serum IL-1β in mice.…”

“…Our study showed that subjects with a high total arsenic concentration in their urine had a high odds ratio (OR) for RCC 8 , even if they are exposed to low arsenic levels. Several studies suggested that arsenic-induced nephrotoxicity may be through activation of inflammasomes and induction of cyclooxygenase-2 (Cox-2) as well as COX-2-derived prostanoids upregulation [9][10][11] . Therefore, whether arsenic induces RCC through an inflammatory response is a topic worthy of discussion.…”

The Role of Protein Tyrosine Phosphatases in Inflammasome Activation

“…For most inflammasome receptors, potential phosphorylation sites have been reported (see ref [47] for a comprehensive overview), but for many of them, it is still unclear whether phosphorylation affects their activity. For example, it has been reported that NLRP1 and AIM2 might serve as substrates for protein kinase R (PKR) [58,59], but it is still debated whether the kinase activity of PKR is required for their activation [60,61]. With respect to the topic of the present review, however, tyrosine phosphorylation has mainly been described for the adaptor molecule ASC and for members of the NLRP family.…”

Old dog, new trick: Trivalent arsenic as an immunomodulatory drug

“…Moreover, As 2 O 3 inhibits NLRP1, NAIP5/NLRC4 inflammasomes in the same subset of cells (Maier, Crown, Liu, Leppla, & Moayeri, 2014). However, in the human keratinocyte cell line and mouse skin tissue, NaAsO 2 promotes IL‐1β and IL‐18 secretion via AIM2 inflammasome activation (Zhang et al, 2016). In addition, the inflammasome NALP2 polymorphism is associated with arsenic‐induced skin lesions in humans (Bhattacharjee et al, 2013).…”