Saturated Fatty Acids Engage an IRE1α-Dependent Pathway to Activate the NLRP3 Inflammasome in Myeloid Cells

Robblee, Megan M.; Kim, Charles C.; Abate, Jess Porter; Valdearcos, Martín; Sandlund, Karin L.M.; Shenoy, Meera K.; Volmer, Romain; Iwawaki, Takao; Koliwad, Suneil K.

doi:10.1016/j.celrep.2016.02.053

Cited by 160 publications

(161 citation statements)

References 59 publications

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“…Similarly, HMGB1, the endogenous danger signal that can stimulate inflammation through activation of pattern recognition receptors (Yanai, et al, 2012) was elevated by aging in the amygdala, but was not elevated with HFD. These results are consistent with previous findings that have shown aging-induced increases, and independently, HFD-induced increases in NLRP3 and HMGB1 gene expression (Fonken, et al, 2016, Robblee, et al, 2016, Sobesky, et al, 2016). We did not find potentiated expression of these two genes when aging and HFD were combined, consistent with previous findings that also failed to show amplified expression of NLRP3 or HMGB1 when HFD was combined with LPS (Sobesky, et al, 2016).…”

Section: Discussionsupporting

confidence: 93%

High-fat diet and aging interact to produce neuroinflammation and impair hippocampal- and amygdalar-dependent memory

Spencer

D’Angelo

Soch

et al. 2017

Neurobiology of Aging

164

129

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More Americans are consuming diets higher in saturated fats and refined sugars than ever before, and based on increasing obesity rates, this is a growing trend among older adults as well. While high saturated fat diet (HFD) consumption has been shown to sensitize the inflammatory response to a subsequent immune challenge in young adult rats, the inflammatory effect of HFD in the already-vulnerable aging brain has not yet been assessed. Here, we explored whether short-term (3 days) consumption of HFD would serve as a neuroinflammatory trigger in aging animals, leading to cognitive deficits. HFD impaired long-term contextual (hippocampal-dependent) and auditory-cued fear (amygdalar-dependent) memory in aged, but not young adult rats. Short-term memory performance for both tasks was intact, suggesting that HFD impairs memory consolidation processes. Microglial markers of activation Iba1 and cd11b were only increased in the aged rats, while MHCII was further amplified by HFD. Furthermore, these HFD-induced long-term memory impairments were accompanied by IL-1β protein increases in both hippocampus and amygdala in aged rats. Central administration of IL-1RA in aged rats following conditioning mitigated both contextual and auditory-cued fear memory impairments caused by HFD, strongly suggesting that IL-1β plays a critical role in these effects. Voluntary wheel running, known to have anti-inflammatory effects in the hippocampus, rescued hippocampal-dependent but not amygdalar-dependent memory impairments caused by HFD. Together, these data suggest that short-term consumption of HFD can lead to memory deficits and significant brain inflammation in the aged animal, and strongly suggest that appropriate diet is crucial for cognitive health.

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Section: Discussionsupporting

confidence: 93%

High-fat diet and aging interact to produce neuroinflammation and impair hippocampal- and amygdalar-dependent memory

Spencer

D’Angelo

Soch

et al. 2017

Neurobiology of Aging

164

129

View full text Add to dashboard Cite

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“…Previous studies showed that ER stress induces inflammasome activation through several mechanisms, including calcium mobilization and the release of reactive oxygen species from damaged mitochondria (mtROS) (44). Because earlier studies from our laboratory and the laboratories of others showed that treatment of macrophages with saturated fatty acids activates IRE1 and because these lipids specifically activated the NLRP3 inflammasome through inducing mtROS production, we sought to investigate this connection further (42,43,45). To this end, we first measured mtROS production in cells exposed to lipotoxic stress in the presence of IRE1 inhibitors.…”

Section: Resultsmentioning

confidence: 97%

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

Tufanlı

Telkoparan-Akillilar

Acosta‐Alvear

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

179

195

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Metaflammation, an atypical, metabolically induced, chronic lowgrade inflammation, plays an important role in the development of obesity, diabetes, and atherosclerosis. An important primer for metaflammation is the persistent metabolic overloading of the endoplasmic reticulum (ER), leading to its functional impairment. Activation of the unfolded protein response (UPR), a homeostatic regulatory network that responds to ER stress, is a hallmark of all stages of atherosclerotic plaque formation. The most conserved ERresident UPR regulator, the kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1), is activated in lipid-laden macrophages that infiltrate the atherosclerotic lesions. Using RNA sequencing in macrophages, we discovered that IRE1 regulates the expression of many proatherogenic genes, including several important cytokines and chemokines. We show that IRE1 inhibitors uncouple lipid-induced ER stress from inflammasome activation in both mouse and human macrophages. In vivo, these IRE1 inhibitors led to a significant decrease in hyperlipidemia-induced IL-1β and IL-18 production, lowered T-helper type-1 immune responses, and reduced atherosclerotic plaque size without altering the plasma lipid profiles in apolipoprotein E-deficient mice. These results show that pharmacologic modulation of IRE1 counteracts metaflammation and alleviates atherosclerosis.endoplasmic reticulum stress | unfolded protein response | metaflammation | lipotoxicity | atherosclerosis C omplex molecular interactions between environment, diet, and genetics that take place at the metabolic and immune interface provoke a low-grade, chronic inflammatory responsemetaflammation-that engages cells of the immune system (macrophages, neutrophils, and lymphocytes) and metabolic tissues (adipocytes, hepatocytes, and pancreatic cells) (1). An important primer for metaflammation is chronic metabolic overloading of organelles, such as the endoplasmic reticulum (ER) and mitochondria, which results in impairment of their functions (2).The ER serves essential cellular functions that include the synthesis and folding of secreted and transmembrane proteins, calcium storage, and lipid synthesis for membrane biogenesis or energy storage. Disruption of any of these functions leads to ER stress and the subsequent activation of an elaborate network of adaptive responses, collectively known as the unfolded protein response (UPR) (3). The UPR reestablishes homeostasis through both transcriptional and translational layers of control. The UPR signals through three mechanistically distinct branches that are initiated by the ER-resident protein folding sensors inositolrequiring enzyme 1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) (3).IRE1 controls the phylogenetically most conserved branch of the UPR found from fungi to metazoans. It has an ER-lumenal sensor domain that recognizes unfolded peptides and cytosolic kinase and endoribonuclease (RNase) domains that relay the information to downstrea...

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“…Which lipid species mediate the activation of the UPR during lipolysis in the absence of DGAT activity is unknown. One possibility is changes in ER phospholipid composition (e.g., a higher degree of saturated fatty acid side chains), which trigger activation of the Ire1 and PERK UPR sensors (Robblee et al, 2016; Volmer and Ron, 2015; Volmer et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

Triglyceride Synthesis by DGAT1 Protects Adipocytes from Lipid-Induced ER Stress during Lipolysis

et al. 2017

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SUMMARY Triglyceride (TG) storage in adipose tissue provides the major reservoir for metabolic energy in mammals. During lipolysis, fatty acids (FAs) are hydrolyzed from adipocyte TG stores and transported to other tissues for fuel. For unclear reasons, a large portion of hydrolyzed FAs in adipocytes is re-esterified to TGs in a “futile”, ATP-consuming, energy dissipating cycle. Here we show that FA re-esterification during adipocyte lipolysis is mediated by DGAT1, an ER-localized DGAT enzyme. Surprisingly, this re-esterification cycle does not preserve TG mass, but instead functions to protect the ER from lipotoxic stress and related consequences, such as adipose tissue inflammation. Our data reveal an important role for DGAT activity and TG synthesis generally in averting ER stress and lipotoxicity, with specifically DGAT1 performing this function during stimulated lipolysis in adipocytes.

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Saturated Fatty Acids Engage an IRE1α-Dependent Pathway to Activate the NLRP3 Inflammasome in Myeloid Cells

Cited by 160 publications

References 59 publications

High-fat diet and aging interact to produce neuroinflammation and impair hippocampal- and amygdalar-dependent memory

High-fat diet and aging interact to produce neuroinflammation and impair hippocampal- and amygdalar-dependent memory

Targeting IRE1 with small molecules counteracts progression of atherosclerosis

Triglyceride Synthesis by DGAT1 Protects Adipocytes from Lipid-Induced ER Stress during Lipolysis

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