Regulating metabolic inflammation by nutritional modulation
Authors: Hugo Charles-Messance, Kathleen A.J. Mitchelson, Elena De Marco Castro, Frederick J. Sheedy, Helen M. Roche
Journal: Journal of Allergy and Clinical Immunology (2020)

Metabolic inflammation (metaflammation) is characteristic of obesity-related metabolic disorders, associated with increased risk of development of type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), or cardiovascular disease. Metaflammation refers to a chronic, low-grade systemic inflammation as opposed to the classical transient and acute inflammatory responses of the innate immune system. Metaflammation is driven by a range of adverse dietary factors, including saturated fatty acids and some sugars, suggesting that certain dietary triggers may be particularly relevant beyond simple excessive dietary intake presenting as obesity. Importantly, obese patients with diabetes have a higher risk of infection and display gut microbiota profiles characteristic of dysfunctional immunity. Targeting metaflammation has also emerged as a strategy to attenuate metabolic disease. In this review we explore how different nutrition interventions may reconfigure disrupted metabolic inflammation in type 2 diabetes and nonalcoholic fatty liver disease by reestablishing a conventional proinflammatory program in innate immune cells and/or correcting dysbiosis to dampen systemic inflammation. We begin by reviewing concepts of metabolic inflammation relating to IL-1β inflammation and how it is induced by dietary and/or metabolic stressors. We then explore whether and how dietary interventions may attenuate processes pertaining to metaflammation, either directly or indirectly via the microbiome. Hence, we hope to bring new perspectives to alleviate the metaflammation typifying metabolic disease. Metabolic inflammation (metaflammation) is characteristic of obesity-related metabolic disorders, associated with increased risk of development of type 2 diabetes, nonalcoholic fatty liver disease (NAFLD), or cardiovascular disease. Metaflammation refers to a chronic, low-grade systemic inflammation as opposed to the classical transient and acute inflammatory responses of the innate immune system. Metaflammation is driven by a range of adverse dietary factors, including saturated fatty acids and some sugars, suggesting that certain dietary triggers may be particularly relevant beyond simple excessive dietary intake presenting as obesity. Importantly, obese patients with diabetes have a higher risk of infection and display gut microbiota profiles characteristic of dysfunctional immunity. Targeting metaflammation has also emerged as a strategy to attenuate metabolic disease. In this review we explore how different nutrition interventions may reconfigure disrupted metabolic inflammation in type 2 diabetes and nonalcoholic fatty liver disease by reestablishing a conventional proinflammatory program in innate immune cells and/or correcting dysbiosis to dampen systemic inflammation. We begin by reviewing concepts of metabolic inflammation relating to IL-1β inflammation and how it is induced by dietary and/or metabolic stressors. We then explore whether and how dietary interventions may attenuate processes pertaining to metaflammation, either directly or indirectly via the microbiome. Hence, we hope to bring new perspectives to alleviate the metaflammation typifying metabolic disease. The Westernized lifestyle, characterized by an energy-dense Western diet (WD) high in fat and simple sugars coincident with a sedentary lifestyle, is associated with chronic metabolic inflammation, termed metaflammation.1Hotamisligil G.S. Inflammation, metaflammation and immunometabolic disorders.Nature. 2017; 542: 177-185Crossref PubMed Scopus (551) Google Scholar Metaflammation is notably observed in obese individuals despite the absence of infection. Persistent metaflammation has been associated with the development of severe comorbidities, such as type 2 diabetes (T2D),2Xu H. Barnes G.T. Yang Q. Tan G. Yang D. Chou C.J. et al.Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.J Clin Invest. 2003; 112: 1821-1830Crossref PubMed Scopus (4572) Google Scholar nonalcoholic fatty liver disease (NAFLD),3Asrih M. Jornayvaz F.R. Inflammation as a potential link between nonalcoholic fatty liver disease and insulin resistance.J Endocrinol. 2013; 218: R25-R36Crossref PubMed Scopus (157) Google Scholar and atherosclerosis.4Moore K.J. Sheedy F.J. Fisher E.A. Macrophages in atherosclerosis: a dynamic balance.Nat Rev Immunol. 2013; 13: 709-721Crossref PubMed Scopus (1062) Google Scholar NAFLD, a chronic and evolving liver complication, has a high prevalence of 60% in patients with T2D5Williamson R.M. Price J.F. Glancy S. Perry E. Nee L.D. Hayes P.C. et al.Prevalence of and risk factors for hepatic steatosis and nonalcoholic fatty liver disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study.Diabetes Care. 2011; 34: 1139-1144Crossref PubMed Scopus (207) Google Scholar; therefore, in this review we consider the existing links between metaflammation and NAFLD alongside T2D, and to a lesser extent, atherosclerotic disease. Subacute proinflammatory cytokine signatures during metaflammation are strongly implicated in disrupted insulin signaling6Jager J. Grémeaux T. Cormont M. Le Marchand-Brustel Y. Tanti J.F. Interleukin-1β-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression.Endocrinology. 2007; 148: 241-251Crossref PubMed Scopus (434) Google Scholar and metabolic dysregulation in obesity, T2D, and NAFLD. As such, interrupting proinflammatory triggers or anti-inflammatory therapies may be important considerations. In particular, IL-1 is a key mediator of metaflammation. IL-1β priming and production is tightly controlled at the level of pro–IL-1β and NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) expression and inflammasome assembly, both of which are mechanisms that are sophisticatedly regulated by recognition of various diet-derived danger signals, with subsequent coordination of intracellular signaling. Thus, the NLRP3 inflammasome is believed to act as an important platform coordinating metabolic inflammation and a variety of metabolic disruptions related to T2D and/or NAFLD progression. One of the first studies targeting IL-1 receptor signaling with the antagonist anakinra improved glycemic control and reduced systemic inflammation in T2D.7Larsen C.M. Faulenbach M. Vaag A. Vølund A. Ehses J.A. Seifert B. et al.Interleukin-1-receptor antagonist in type 2 diabetes mellitus.N Engl J Med. 2007; 356: 1517-1526Crossref PubMed Scopus (1248) Google Scholar Nevertheless, there is not yet a consistent relationship between IL-1 blockade and risk of cardiovascular disease (CVD) and T2D. The CANTOS trial demonstrated that the recombinant anti–IL-1β antibody canakinumab significantly reduced recurrent CVD, independent of any improvement in lipid concentrations.8Ridker P.M. Everett B.M. Thuren T. MacFadyen J.G. Chang W.H. Ballantyne C. et al.Antiinflammatory therapy with canakinumab for atherosclerotic disease.N Engl J Med. 2017; 377: 1119-1131Crossref PubMed Scopus (2424) Google Scholar Subsequent post hoc analysis of efficacy in diabetes showed that although IL-1β inhibition reduced systemic inflammatory markers and CVD events in subjects with and without diabetes, IL-1β blockade did not reduce incident diabetes. Given the heterogeneity in the field, in this review we address potential interactions between metabolism, nutrition, and NLRP3 inflammasome regulation within metaflammation-associated metabolic disorders. Next, we describe the nature and contribution of several dietary drivers of metaflammation. Finally, we examine whether nutritional intervention may be manipulated to dampen and/or reverse this state of persistent low-grade inflammation. The mechanisms leading to induction of metaflammation in obesity are partially elucidated. Innate immune cells, specifically monocytes and macrophages, are critical to the initial activation and persistence of metabolic inflammation. These cells express pattern recognition receptors (PRRs) that can detect various danger signals. There are several classes of PRRs, and we will focus mainly on Toll-like receptors (TLRs) and NLRs. TLRs normally recognize pathogen-associated molecular patterns (PAMPs), which are evolutionarily conserved structures expressed by pathogens such as LPS. NLRs recognize damage-associated molecular patterns (DAMPs) and directly sense danger signals of metabolic stress (eg, extracellular ATP, cholesterol, or urate crystals), as well as specific dietary metabolites. The coordinated action between TLRs and NLRs mediates the inflammatory response and antipathogen immune defenses with regard to inflammasome activation.9Broz P. Dixit V.M. Inflammasomes: mechanism of assembly, regulation and signalling.Nat Rev Immunol. 2016; 16: 407-420Crossref PubMed Scopus (762) Google Scholar To date, NLRP3 remains the best-characterized inflammasome. NLRP3 and pro–IL-1β expression are induced by TLR-mediated "priming" signals, after which secondary NLR-activating signals elicit NLRP3 oligomerization with apoptosis-associated speck-like protein containing a CARD (ASC) adaptor proteins.10Swanson K.V. Deng M. Ting J.P.-Y. The NLRP3 inflammasome: molecular activation and regulation to therapeutics.Nat Rev Immunol. 2019; 19: 477-489Crossref PubMed Scopus (329) Google Scholar Caspase-1 is then recruited via caspase recruitment domain (CARD) domain interactions and undergoes autocatalytic activation to promote the secretion of mature inflammatory cytokines (IL-1β and IL-18).10Swanson K.V. Deng M. Ting J.P.-Y. The NLRP3 inflammasome: molecular activation and regulation to therapeutics.Nat Rev Immunol. 2019; 19: 477-489Crossref PubMed Scopus (329) Google Scholar Thus, the accumulation of DAMPs in a pathogenic context such as obesity can instruct cytokine production and favor characteristics of metaflammation via inflammasome activation. Interestingly, the unique innate immune sensor NLRP3 senses obesity-associated danger signals.11Vandanmagsar B. Youm Y.H. Ravussin A. Galgani J.E. Stadler K. Mynatt R.L. et al.The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance.Nat Med. 2011; 17: 179-189Crossref PubMed Scopus (1374) Google Scholar Indeed, in animals exposed to a high-fat diet (HFD) or obese leptin-deficient animals, such signals induce a proinflammatory response in innate immune cells located in the adipose tissue via induction of the NLRP3/IL-1β axis.11Vandanmagsar B. Youm Y.H. Ravussin A. Galgani J.E. Stadler K. Mynatt R.L. et al.The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance.Nat Med. 2011; 17: 179-189Crossref PubMed Scopus (1374) Google Scholar IL-1β induces insulin resistance by serine phosphorylation of IRS1 in target tissues, affecting glucose and lipid metabolism as well as promoting inflammation via TNF-α production.12Wen H. Gris D. Lei Y. Jha S. Zhang L. Huang M.T.H. et al.Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling.Nat Immunol. 2011; 12: 408-415Crossref PubMed Scopus (1023) Google Scholar Consistent with this, the clustered regularly interspaced short palindromic repeats/Cas9 method has been successfully used to disrupt NLRP3 expression in macrophages, increasing insulin sensitivity and reducing adipose inflammation in an HFD-induced T2D mouse model.13Xu C. Lu Z. Luo Y. Liu Y. Cao Z. Shen S. et al.Targeting of NLRP3 inflammasome with gene editing for the amelioration of inflammatory diseases.Nat Commun. 2018; 9: 4092Crossref PubMed Scopus (40) Google Scholar Regarding the liver, inflammation and NLRP3 inflammasome are recognized as important factors implicated in NAFLD persistence.14Wree A. McGeough M.D. Peña C.A. Schlattjan M. Li H. Inzaugarat M.E. et al.NLRP3 inflammasome activation is required for fibrosis development in NAFLD.J Mol Med. 2014; 92: 1069-1082Crossref PubMed Scopus (187) Google Scholar Animals fed an HFD display inflammasome activation and steatohepatitis,15Ganz M. Csak T. Szabo G. High fat diet feeding results in gender specific steatohepatitis and inflammasome activation.World J Gastroenterol. 2014; 20: 8525-8534Crossref PubMed Scopus (67) Google Scholar and therapies targeting NLRP3 inflammasome activation have been successful in preventing NAFLD in mice exposed to an HFD.16Yang G. Lee H.E. Lee J.Y. A pharmacological inhibitor of NLRP3 inflammasome prevents non-alcoholic fatty liver disease in a mouse model induced by high fat diet.Sci Rep. 2016; 6: 24399Crossref PubMed Google Scholar In humans, 1 of the first studies targeting IL-1β signaling used the recombinant human IL-1 receptor antagonist anakinra to inhibit IL-1 receptor, improving glycemia and reducing markers of systemic inflammation in patients with T2D.7Larsen C.M. Faulenbach M. Vaag A. Vølund A. Ehses J.A. Seifert B. et al.Interleukin-1-receptor antagonist in type 2 diabetes mellitus.N Engl J Med. 2007; 356: 1517-1526Crossref PubMed Scopus (1248) Google Scholar However, anakinra treatment did not improve whole-body insulin resistance, suggesting that there is a gap between the preclinical and clinical contexts, a key element of which may be due to the focus on interrupting disease progression in preclinical studies versus on regression in established T2D cohorts. Administration of canakinumab in patients with T2D did not result in improved glycemic control parameters; however, it produced a reduction in glycated hemoglobin17Hensen J. Howard C.P. Walter V. Thuren T. Impact of interleukin-1β antibody (canakinumab) on glycaemic indicators in patients with type 2 diabetes mellitus: results of secondary endpoints from a randomized, placebo-controlled trial.Diabetes Metab. 2013; 39: 524-531Crossref PubMed Scopus (64) Google Scholar and high-sensitivity C-reactive protein levels,18Noe A. Howard C. Thuren T. Taylor A. Skerjanec A. Pharmacokinetic and pharmacodynamic characteristics of single-dose canakinumab in patients with type 2 diabetes mellitus.Clin Ther. 2014; 36: 1625-1637Abstract Full Text Full Text PDF PubMed Google Scholar whereas another study reported no significant effect.19Choudhury R.P. Birks J.S. Mani V. Biasiolli L. Robson M.D. L'Allier P.L. et al.Arterial Effects of canakinumab in patients with atherosclerosis and type 2 diabetes or glucose intolerance.J Am Coll Cardiol. 2016; 68: 1769-1780Crossref PubMed Scopus (50) Google Scholar More clinical trials exploring the potential benefits of anakinra and/or canakinumab administration in such settings are currently being conducted. Moreover, recent data show that dietary components can prime NLRP3-dependent inflammatory pathways in myeloid cells toward metaflammation (as discussed in more detail in the section on metabolic and dietary drivers of metaflammation), and the area of so-called trained immunity is receiving much interest20Christ A. Günther P. Lauterbach M.A.R. Duewell P. Biswas D. Pelka K. et al.Western diet triggers NLRP3-dependent innate immune reprogramming.Cell. 2018; 172: 162-175.e14Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar (Figs 1 and 2). Therefore, we will now discuss the PRR-associated signals linked to metaflammation activation during consumption of a WD, with an emphasis on the inflammasome/IL-1 pathway.Fig 2Dietary fatty acids composition differentially modulates NLRP3 inflammasome activation and IL-1β secretion. SFAs exert proinflammatory functions by priming macrophages, favoring inflammasome assembly and mature IL-1β secretion when synergizing with secondary activating signals. MUFAs, on the other hand, do not enhance proinflammatory cytokine production, and the composition of the n-3/n-6 PUFA ratio in the diet appears to be an important component to understand the beneficial effects driven by particular PUFA compounds, such as EPA or DHA. ASC, Apoptosis-associated speck-like protein containing a CARD.View Large Image Figure ViewerDownload Hi-res image Download (PPT) TLR signaling clearly is implicated in metaflammation. TLRs display increased activity and expression in obese patients with diabetes21Jialal I. Huet B.A. Kaur H. Chien A. Devaraj S. Increased toll-like receptor activity in patients with metabolic syndrome.Diabetes Care. 2012; 35: 900-904Crossref PubMed Scopus (124) Google Scholar and individuals with nonalcoholic steatohepatitis (NASH).22Sharifnia T. Antoun J. Verriere T.G.C. Suarez G. Wattacheril J. Wilson K.T. et al.Hepatic TLR4 signaling in obese NAFLD.Am J Physiol Gastrointest Liver Physiol. 2015; 309: G270-G278Crossref PubMed Scopus (79) Google Scholar Saturated fatty acids (SFAs) and their derivatives and dietary consequences (eg, ceramides, cholesterol, etc) enhance TLR4 signaling and activity in adipose tissue23Suganami T. Mieda T. Itoh M. Shimoda Y. Kamei Y. Ogawa Y. Attenuation of obesity-induced adipose tissue inflammation in C3H/HeJ mice carrying a Toll-like receptor 4 mutation.Biochem Biophys Res Commun. 2007; 354: 45-49Crossref PubMed Scopus (167) Google Scholar and liver24Shi H. Kokoeva M.V. Inouye K. Tzameli I. Yin H. Flier J.S. TLR4 links innate immunity and fatty acid-induced insulin resistance.J Clin Invest. 2006; 116: 3015-3025Crossref PubMed Scopus (2338) Google Scholar macrophages, and they favor NLRP3 inflammasome activation in atherosclerotic plaques alongside oxidized low-density lipoproteins (oxLDLs).25Rhoads J.P. Lukens J.R. Wilhelm A.J. Moore J.L. Mendez-Fernandez Y. Kanneganti T.-D. et al.Oxidized low-density lipoprotein immune complex priming of the Nlrp3 inflammasome involves TLR and FcγR cooperation and is dependent on CARD9.J Immunol. 2017; 198: 2105-2114Crossref PubMed Scopus (37) Google Scholar In hyperglycemic conditions, the engagement of TLRs by SFAs exacerbates expression of proinflammatory genes via generation of reactive oxygen species (ROSs) and nuclear factor-κB (NF-κB) activity.26Dasu M.R. Devaraj S. Park S. Jialal I. Increased Toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects.Diabetes Care. 2010; 33: 861-868Crossref PubMed Scopus (358) Google Scholar Although SFAs were thought to directly engage with TLR4, a very recent study demonstrated that LPS-induced macrophage metabolic reprogramming synergizes with SFA-induced c-Jun N-terminal kinase (JNK) protein activation to promote inflammatory cytokine release.27Lancaster G.I. Langley K.G. Berglund N.A. Kammoun H.L. Reibe S. Estevez E. et al.Evidence that TLR4 is not a receptor for saturated fatty acids but mediates lipid-induced inflammation by reprogramming macrophage metabolism.Cell Metab. 2018; 27: 1096-1110.e5Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar Interestingly, other metabolic signals, including SFA-derivative ceramides or cholesterol crystals,28Duewell P. Kono H. Rayner K.J. Sirois C.M. Vladimer G. Bauernfeind F.G. et al.NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals.Nature. 2010; 464: 1357-1361Crossref PubMed Scopus (1952) Google Scholar are thought to be TLR-activating ligands and could therefore potentially prime NLRP3. Whether the plethora of diverse metabolites present in the obese diabetic state act as direct ligands for a variety of PRRs or underlie a common activating danger signal requires clarification and adds to the complexity underlying activation of metaflammation. Another compounding complexity in relation to potential metabolic agonists is the putative role of the gut microbiome (which is altered in obesity) in conjunction with compromised intestinal barrier integrity29Martinez-Medina M. Denizot J. Dreux N. Robin F. Billard E. Bonnet R. et al.Western diet induces dysbiosis with increased e coli in CEABAC10 mice, alters host barrier function favouring AIEC colonisation.Gut. 2014; 63: 116-124Crossref PubMed Scopus (224) Google Scholar and metabolic endotoxemia. Patients with diabetes display high levels of circulating LPS.30Amar J. Chabo C. Waget A. Klopp P. Vachoux C. Bermúdez-Humarán L.G. et al.Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment.EMBO Mol Med. 2011; 3: 559-572Crossref PubMed Scopus (432) Google Scholar Thus, systemic endotoxins may engage with TLRs26Dasu M.R. Devaraj S. Park S. Jialal I. Increased Toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects.Diabetes Care. 2010; 33: 861-868Crossref PubMed Scopus (358) Google Scholar and precipitate proinflammatory inflammasome activation. Consistent with this, treatment with LPS, a well-characterized TLR4 agonist and a potent inducer of NLRP3 expression, also elicits adipocyte insulin resistance when cocultured with macrophages31Pekala P. Kawakami M. Vine W. Daniel Lane M. Cerami A. Studies of insulin resistance in adipocytes induced by macrophage mediator.J Exp Med. 1983; 157: 1360-1365Crossref PubMed Google Scholar or SFA-treated dendritic cells.32Reynolds C.M. Mcgillicuddy F.C. Harford K.A. Finucane O.M. Mills K.H.G. Roche H.M. Dietary saturated fatty acids prime the NLRP3 inflammasome via TLR4 in dendritic cells-implications for diet-induced insulin resistance.Mol Nutr Food Res. 2012; 56: 1212-1222Crossref PubMed Scopus (102) Google Scholar Additionally, fatty acids (FAs) and endotoxins have been reported to synergistically drive NLRP3 inflammasome activation.33Csak T. Ganz M. Pespisa J. Kodys K. Dolganiuc A. Szabo G. Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells.Hepatology. 2011; 54: 133-144Crossref PubMed Scopus (363) Google Scholar Second hit signals generated after LPS-mediated inflammasome priming can be provided by different intracellular metabolites. Generation of ROSs and purinergic receptor 7 (P2RX7) extracellular ATP sensing mediating K+ efflux can activate primed NLRP3,34Muñoz-Planillo R. Kuffa P. Martínez-Colón G. Smith B.L. Rajendiran T.M. Núñez G. K+ efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter.Immunity. 2013; 38: 1142-1153Abstract Full Text Full Text PDF PubMed Scopus (824) Google Scholar and advanced glycation end products (ie, glycotoxins produced in hyperglycemic individuals) can also act as DAMPs and promote NLRP3 activation via AMP-activated protein kinase (AMPK) inhibition and ROS production. Finally, caspase-11–mediated pyroptosis in response to intracellular LPS can induce noncanonic inflammasome activation and mature IL-1β secretion.35Pilla D.M. Hagar J.A. Haldar A.K. Mason A.K. Degrandi D. Pfeffer K. et al.Guanylate binding proteins promote caspase-11-dependent pyroptosis in response to cytoplasmic LPS.Proc Natl Acad Sci U S A. 2014; 111: 6046-6051Crossref PubMed Scopus (177) Google Scholar In the liver, ablation of adipocyte JNK-1 expression prevents hepatic insulin resistance in obese animals,36Sabio G. Das M. Mora A. Zhang Z. Jun J.Y. Hwi J.K. et al.A stress signaling pathway in adipose tissue regulates hepatic insulin resistance.Science. 2008; 322: 1539-1543Crossref PubMed Scopus (398) Google Scholar suggesting that TLR-mediated inflammation acts as one of the initial events contributing to NAFLD. However, little is known regarding NRLP3 inflammasome assembly and activation in hepatocytes during NAFLD. We know that endoplasmic reticulum (ER) stress appears to link inflammation and hepatocyte death, favoring the progression of NAFLD.37Lebeaupin C. Proics E. De Bieville C.H.D. Rousseau D. Bonnafous S. Patouraux S. et al.ER stress induces NLRP3 inflammasome activation and hepatocyte death.Cell Death Dis. 2015; 6e1879Crossref PubMed Google Scholar LPS-induced ER stress can trigger activation of caspase-11 and caspase-1 in turn, leading to the maturation and production of IL-1β.32Reynolds C.M. Mcgillicuddy F.C. Harford K.A. Finucane O.M. Mills K.H.G. Roche H.M. Dietary saturated fatty acids prime the NLRP3 inflammasome via TLR4 in dendritic cells-implications for diet-induced insulin resistance.Mol Nutr Food Res. 2012; 56: 1212-1222Crossref PubMed Scopus (102) Google Scholar,38Endo M. Mori M. Akira S. Gotoh T. C/EBP homologous protein (CHOP) is crucial for the induction of caspase-11 and the pathogenesis of lipopolysaccharide-induced inflammation.J Immunol. 2006; 176: 6245-6253Crossref PubMed Google Scholar Using a selective inhibitor of NLRP3 clearly improved fibrosis and NAFLD features in obese diabetic mice39Mridha A.R. Wree A. Robertson A.A.B. Yeh M.M. Johnson C.D. Van Rooyen D.M. et al.NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice.J Hepatol. 2017; 66: 1037-1046Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar; the authors hypothesized that this protective effect could be attributed to the blockade of cholesterol crystal–induced inflammation. As a matter of fact, ER stress and oxidative stress appear to play an important role in the pathogenesis of metabolic disease, at the intersection of perception of danger signals and inflammasome activation. A very elegant study published in 2014 by Özcan et al established how obesity-induced ER stress can lead to JNK hyperactivation and IRS1 phosphorylation, opening new therapeutic perspectives on preventing insulin resistance in obese individuals.40Özcan U. Cao Q. Yilmaz E. Lee A.H. Iwakoshi N.N. Özdelen E. et al.Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes.Science. 2004; 306: 457-461Crossref PubMed Scopus (2647) Google Scholar More recently, HFD-induced obesity has been shown to induce osteoarthritis-promoting ER stress in mice, further highlighting the importance of considering the contribution of ER stress to the progression of metaflammation in the context of obesity.41Tan L. Harper L. McNulty M.A. Carlson C.S. Yammani R.R. High-fat diet induces endoplasmic reticulum stress to promote chondrocyte apoptosis in mouse knee joints.FASEB J. 2020; 34: 5818-5826Crossref PubMed Scopus (0) Google Scholar Consistent with these discoveries, a significant increase in ER stress markers associated with adipose tissue inflammation appears in mice after 16 weeks of an HFD, which can be reversed by the administration of chemical chaperons.42Kawasaki N. Asada R. Saito A. Kanemoto S. Imaizumi K. Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue.Sci Rep. 2012; 2: 799Crossref PubMed Scopus (192) Google Scholar Indeed, ER stress is known to induce the activation of the unfolded protein response (UPR), which aims at restoring cell function and production of adequatly folded proteins by using chaperons. In chronically unresolved ER stress, the persistence of UPRs inevitably triggers a set of downstream signaling, leading to induction of apoptosis via JNK phosphorylation and production of proinflammatory cytokines via NF-κB induction and ultimately conducting to insulin resistance.43Chen L. Chen R. Wang H. Liang F. Mechanisms linking inflammation to insulin resistance.Int J Endocrinol. 2015; 2015508409Crossref PubMed Scopus (208) Google Scholar The UPR as a signaling pathway comprises the inositol-requiring enzyme 1 (IRE1), the PKR-like ER kinase (PERK), and the activating transcription factor 6 (ATF6). These signaling pathways have been associated with mechanisms pertaining to inflammation under ER stress,44Martinon F. Chen X. Lee A.H. Glimcher L.H. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages.Nat Immunol. 2010; 11: 411-418Crossref PubMed Scopus (567) Google Scholar although it remains less evident for ATF6. The IRE1α ER stress sensor induces mitochondrial damage through ASC-independent NLRP3 induction and caspase-2 release, thereby promoting inflammation.45Bronner D.N. Abuaita B.H. Chen X. Fitzgerald K.A. Nuñez G. He Y. et al.Endoplasmic reticulum stress activates the inflammasome via NLRP3- and caspase-2-driven mitochondrial damage.Immunity. 2015; 43: 451-462Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar Interestingly, the contribution of UPR to ER stress–induced NLRP3 activation remains controverted, as suggested by an in vitro study,46Menu P. Mayor A. Zhou R. Tardivel A. Ichijo H. Mori K. et al.ER stress activates the NLRP3 inflammasome via an UPR-independent pathway.Cell Death Dis. 2012; 3: e261Crossref PubMed Scopus (192) Google Scholar although this study did not integrate the complexity and diversity of the stress signals that exist in vivo in animals or humans with diabetes. Indeed, in an environment of excessive FAs, coincident with TLR agonists and mitochondrial ROS production, both features of metabolic disease can promote UPR engagement and inflammation exacerbation.47Mogilenko D.A. Haas J.T. L'homme L. Fleury S. Quemener S. Levavasseur M. et al.Metabolic and innate immune cues merge into a specific inflammatory response via the UPR.Cell. 2019; 177: 1201-1216.e19Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar Attenuating the UPR is associated with antioxidative and anti-inflammatory effects,48Zhang C. He S. Li Y. Li F. Liu Z. Liu J. et al.Bisoprolol protects myocardium cells against ischemia/reperfusion injury by attenuating unfolded protein response in rats.Sci Rep. 2017; 7Google Scholar as well as with reduced apoptosis,49Szymański J. Janikiewicz J. Michalska B. Patalas-Krawczyk P. Perrone M. Ziółkowski W. et al.Interaction of mitochondria with the endoplasmic reticulum and plasma membrane in calcium homeostasis, lipid trafficking and mitochondrial structure.Int J Mol Sci. 2017; 18: 1576Crossref PubMed Scopus (0) Google Scholar thus highlighting the role of ER stress–induced UPR in mediating obesity-associated metabolic inflammation and insulin resistance.50Hotami