1 Nature Immunology 2012 Vol: 13(4):352-357. DOI: 10.1038/ni.2228

A role for the NLRP3 inflammasome in metabolic diseases[mdash]did Warburg miss inflammation[quest]

The inflammasome is a protein complex that comprises an intracellular sensor (typically a Nod-like receptor), the precursor procaspase-1 and the adaptor ASC. Inflammasome activation leads to the maturation of caspase-1 and the processing of its substrates, interleukin 1β (IL-1β) and IL-18. Although initially the inflammasome was described as a complex that affects infection and inflammation, subsequent evidence has suggested that inflammasome activation influences many metabolic disorders, including atherosclerosis, type 2 diabetes, gout and obesity. Another feature of inflammation in general and the inflammasome specifically is that the activation process has a profound effect on aerobic glycolysis (the 'Warburg effect'). Here we explore how the Warburg effect might be linked to inflammation and inflammasome activation.

Mentions
Figures
Figure 1: A model for the pathogenesis of type 2 diabetes involving adipose tissue, the pancreas and NLRP3.In adipose tissue, high concentrations of saturated free fatty acids such as palmitate lead to lower activity of AMP-activated kinase (AMPK), a central regulator of energy biosynthesis and lipid metabolism, which leads to defective autophagy of mitochondria ('mitophagy'). The accumulation of dysfunctional mitochondria then enhances mitochondrial generation of ROS and the release of mitochondrial DNA into the cytosol, both of which promote activation of the NLRP3 inflammasome and release of IL-1β (p17 subunit). A high concentration of glucose has been shown to promote the production of IL-1β by pancreatic beta cells but not by macrophages. The active IL-1β induces the activation of Jnk and IκB kinase through the IL-1 receptor (IL-1R), which impairs engagement of the insulin receptor (IR) by insulin receptor substrate 1 (IRS1) and the PI(3)K–kinase Akt signaling pathway. In the pancreas, the accumulation of IAPP activates the NLRP3 inflammasome and promotes the release IL-1β from macrophages, which causes beta-cell dysfunction and death. MAPK, mitogen-activated protein kinase; T2D, type 2 diabetes. Figure 2: Metabolic fluxes, NLRP3 and IL-1β.Hyperlipidemia, in the form of saturated fatty acids such as palmitate, activates the NLRP3 inflammasome, which leads to the activation of caspase-1 and processing of pro-IL-1β. Impaired mitochondrial metabolism, including lower β-oxidation of fatty acids, could promote this process, as does the production of ROS. Activation of TLR4 by LPS or minimally modified oxidized low-density lipoprotein (mmLDL) promotes glycolysis through the induction of enzymes such as uPFK2, which leads to enhanced ATP production and nucleotide biosynthesis through the pentose phosphate pathway. Purines, including uric acid, could be overproduced through this process, leading to activation of the NLRP3 inflammasome. IL-1β gives rise to insulin resistance, causing enhanced IAPP production, which in turn further activates NLRP3. Insulin resistance in liver and muscle might spare glucose for macrophages. TCA, tricarboxylic acid.
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References
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    • . . . As studies have suggested that the aberrant accumulation and activation of lymphocytes (including both T cells and B cells) in adipose tissue impairs insulin sensitivity in obesity-induced insulin resistance36, 37, 38, 39, 40, activation of the NLRP3 inflammasome might lead to lymphocyte accumulation and activation in obesity and insulin resistance . . .
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    • . . . As studies have suggested that the aberrant accumulation and activation of lymphocytes (including both T cells and B cells) in adipose tissue impairs insulin sensitivity in obesity-induced insulin resistance36, 37, 38, 39, 40, activation of the NLRP3 inflammasome might lead to lymphocyte accumulation and activation in obesity and insulin resistance . . .
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    • . . . As studies have suggested that the aberrant accumulation and activation of lymphocytes (including both T cells and B cells) in adipose tissue impairs insulin sensitivity in obesity-induced insulin resistance36, 37, 38, 39, 40, activation of the NLRP3 inflammasome might lead to lymphocyte accumulation and activation in obesity and insulin resistance . . .
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    • . . . The mechanisms by which urate crystals cause inflammatory arthritis and IL-1β is generated remained largely unknown until the NLRP3 inflammasome was identified as the link between urate crystals and gout49 . . .
    • . . . Although it has been well documented that crystal structures such as monosodium urate, silica, asbestos and alum induce NLRP3 inflammasome–dependent cleavage of caspase-1 and IL-1β or IL-18, particularly in vitro49, 50, 51, 52, studies have shown NLRP3 inflammasome–independent effects of uric acid, silica and alum in the development of T helper type 2 (TH2) immune responses and TH2 cell–associated immunoglobulin E responses68, 69 . . .
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    • . . . This is consistent with the induction of NLRP3 inflammasome activation by other crystals, such as monosodium urate, silica, asbestos and alum49, 50, 51, 52 . . .
    • . . . Although it has been well documented that crystal structures such as monosodium urate, silica, asbestos and alum induce NLRP3 inflammasome–dependent cleavage of caspase-1 and IL-1β or IL-18, particularly in vitro49, 50, 51, 52, studies have shown NLRP3 inflammasome–independent effects of uric acid, silica and alum in the development of T helper type 2 (TH2) immune responses and TH2 cell–associated immunoglobulin E responses68, 69 . . .
  51. Hornung, V. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization Nat. Immunol. 9, 847-856 (2008) .
    • . . . This is consistent with the induction of NLRP3 inflammasome activation by other crystals, such as monosodium urate, silica, asbestos and alum49, 50, 51, 52 . . .
    • . . . Although it has been well documented that crystal structures such as monosodium urate, silica, asbestos and alum induce NLRP3 inflammasome–dependent cleavage of caspase-1 and IL-1β or IL-18, particularly in vitro49, 50, 51, 52, studies have shown NLRP3 inflammasome–independent effects of uric acid, silica and alum in the development of T helper type 2 (TH2) immune responses and TH2 cell–associated immunoglobulin E responses68, 69 . . .
  52. Eisenbarth, S.C.; Colegio, O.R.; O'Connor, W.; Sutterwala, F.S.; Flavell, R.A. Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants Nature 453, 1122-1126 (2008) .
    • . . . This is consistent with the induction of NLRP3 inflammasome activation by other crystals, such as monosodium urate, silica, asbestos and alum49, 50, 51, 52 . . .
    • . . . Although it has been well documented that crystal structures such as monosodium urate, silica, asbestos and alum induce NLRP3 inflammasome–dependent cleavage of caspase-1 and IL-1β or IL-18, particularly in vitro49, 50, 51, 52, studies have shown NLRP3 inflammasome–independent effects of uric acid, silica and alum in the development of T helper type 2 (TH2) immune responses and TH2 cell–associated immunoglobulin E responses68, 69 . . .
  53. Menu, P. Atherosclerosis in ApoE-deficient mice progresses independently of the NLRP3 inflammasome Cell Death Dis. 2, e137 (2011) .
    • . . . However, the crucial role of the NLRP3 inflammasome in atherosclerosis has been challenged by another study of double-mutant mice generated by crossing Apoe−/− mice with Nlrp3−/−, Pycard−/− or Casp1−/− mice53 . . .
    • . . . The difference between those two studies30, 53 is the investigation of a hematopoietic cell–derived NLRP3 inflammasome versus a whole body–derived NLRP3 inflammasome in the development of atherosclerosis . . .
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    • . . . The NLRP3 inflammasome may also function in the stromal compartment to regulate disease progression in addition to functioning the hematopoietic compartment, especially in colitis and colitis-associated cancer54, 55 . . .
    • . . . For example, uric acid is released in the airways of asthmatic patients and allergen-challenged mice and promotes TH2 cell immune responses by activating dendritic cells through signaling pathways of the kinases Syk and PI(3)Kδ54 . . .
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    • . . . Both of these studies have found that NLRP3 has no effect68, 69 . . .
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