Oxysterol Restraint of Cholesterol Synthesis Prevents AIM2 Inflammasome Activation

Abstract

Summary Type I interferon restrains interleukin-1β (IL-1β)-driven inflammation in macrophages by upregulating cholesterol-25-hydroxylase (Ch25h) and repressing SREBP transcription factors. However, the molecular links between lipid metabolism and IL-1β production remain obscure. Here we demonstrate that production of 25-hydroxycholesterol (25-HC) by macrophages is required to prevent inflammasome activation by the DNA sensor protein absent in melanoma 2 (AIM2). We find that in response to bacterial infection or lipopolysaccharide (LPS) stimulation, macrophages upregulate Ch25h to maintain repression of SREBP2 activation and cholesterol synthesis. Increasing macrophage cholesterol content is sufficient to trigger IL-1β release in a crystal-independent but AIM2-dependent manner. Ch25h-deficiency results in cholesterol-dependent reduced mitochondrial respiratory capacity and release of mitochondrial DNA into the cytosol. Ch25h−/−Aim2−/− rescues the increased inflammasome activity observed in Ch25h−/−. Therefore, activated macrophages utilize 25-HC in an anti-inflammatory circuit that maintains mitochondrial integrity and prevents spurious AIM2 inflammasome activation.

Aged insulin resistant macrophages reveal dysregulated cholesterol biosynthesis, a pro-inflammatory profile and reduced foam cell formation capacity

“…S2B). In addition, cholesterol accumulation in macrophages has been linked to inflammasome activation 25 .…”

“…Recent evidence has emerged that macrophage lipid metabolism and inflammatory response are intimately linked. For instance, down regulation of the macrophage cholesterol biosynthesis pathway can activate interferon (IFN) signalling 24 and cholesterol accumulation can activate the inflammasome response 25 . Furthermore, a modified product of cholesterol biosynthesis downstream of the cholesterol pool, 25-hydroxycholesterol (25-OHC), has potent antiviral affects 26 and promotes foam cell formation 27a critical step in the initiation and progression of atherosclerosis 28 .…”

Metabolic regulation of inflammasomes in inflammation

“…95 Interestingly, SCAP-SREBP2 translocation, which shows a positive function in both NLRP3 inflammasome activity and cholesterol biosynthesis, can be inhibited by 25-HC or cholesterol overexposure, suggesting 25-HC and cholesterol may also act as inhibitors of NLRP3 inflammasome activation in LPS-treated BMDMs 96 in contrast to numerous studies showing the strong ability of cholesterol to promote inflammasome activation. 91,97 Collectively, the different observed effects of these two substances may be associated with different stages of the inflammatory response and different types of inflammasomes as the upregulation of 25-HC is known to inhibit AIM2 inflammasome activation through suppressing cholesterol biosynthesis, but its effect on NLRP3 inflammasome activation is ambiguous so far. 97 Bile acid, an important inflammatory mediator derived from oxysterols, negatively regulates nigericin-induced NLRP3 inflammasome activation through the transmembrane Gprotein-coupled receptor-5 (TGR5)-cAMP-PKA axis in non-differentiated BMDMs.…”

“…91,97 Collectively, the different observed effects of these two substances may be associated with different stages of the inflammatory response and different types of inflammasomes as the upregulation of 25-HC is known to inhibit AIM2 inflammasome activation through suppressing cholesterol biosynthesis, but its effect on NLRP3 inflammasome activation is ambiguous so far. 97 Bile acid, an important inflammatory mediator derived from oxysterols, negatively regulates nigericin-induced NLRP3 inflammasome activation through the transmembrane Gprotein-coupled receptor-5 (TGR5)-cAMP-PKA axis in non-differentiated BMDMs. 98 Intriguingly, a recent study reported that cholestasis aggravates sepsis, and bile acids not only potentiate NLRP3 and IL-1b expression but also stimulate NLRP3 inflammasome activation by driving a prolonged Ca 2+ influx.…”

Nucleic Acid Induced Interferon and Inflammasome Responses in Regulating Host Defense to Gastrointestinal Viruses

“…In addition to these IL-10 dependent effects, type I IFNs were also shown to induce the production of 25-hydroxycholesterol (25-HC) that inhibits inflammasomemediated inflammatory responses both in the priming and in the activation stages. Indeed, on the one hand 25-HC was reported to restrain pro-IL-1β expression on the transcriptional level (Reboldi et al, 2014), while on the other hand it was also reported to maintain mitochondrial integrity and as such to prevent the cytosolic release of mitochondrial DNA that could otherwise activate the absent in melanoma 2 (AIM2) inflammasome (Dang et al, 2017). Therefore, it is clear that the concerted actions of type I IFNs and inflammasome responses induced by gastrointestinal viruses could influence mucosal immunity in multiple autocrine and paracrine ways.…”