Saturated fatty acids, obesity, and the nucleotide oligomerization domain–like receptor protein 3 (NLRP3) inflammasome in asthmatic patients

Wood, Lisa G.; Li, Qian; Scott, Hayley A.; Rutting, Sandra; Berthon, Bronwyn S.; Gibson, Peter G.; Hansbro, Philip M.; Williams, Evan J.; Horvat, Jay C.; Simpson, Jodie L.; Young, Paul M.; Oliver, Brian G.; Baines, Katherine J.

doi:10.1016/j.jaci.2018.04.037

Cited by 104 publications

(69 citation statements)

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“…Importantly, gene-environmental interactions play a vital role in the progression of the disease, with specific insults to the respiratory epithelium [7] inducing the release of pro-inflammatory mediators that recruit inflammatory cells to the airways. Exogenous factors such as respiratory viral and bacterial infections, a high-fat diet and/or obesity, air pollution and cigarette smoke exposure have all been linked with severe forms of asthma in adults as well as with exacerbations of the disease [2,[8][9][10][11][12][13][14][15][16][17][18][19][20]. Here, we review the mechanisms of pathogenesis of severe steroid-resistant (SSR) asthma in adults.…”

Section: Introductionmentioning

confidence: 99%

Cellular mechanisms underlying steroid-resistant asthma

et al. 2019

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Severe steroid-resistant asthma is clinically important, as patients with this form of the disease do not respond to mainstay corticosteroid therapies. The heterogeneity of this form of asthma and poor understanding of the pathological mechanisms involved hinder the identification of therapeutic targets and the development of more effective therapies. A major limiting factor in the understanding of severe steroid-resistant asthma is the existence of multiple endotypes represented by different immunological and inflammatory phenotypes, particularly in adults. Several clinical and experimental studies have revealed associations between specific respiratory infections and steroid-resistant asthma in adults. Here, we discuss recent findings from other authors as well as our own studies that have developed novel experimental models for interrogating the association between respiratory infections and severe steroid-resistant asthma. These models have enabled the identification of new therapies using macrolides, as well as several novel disease mechanisms, including the microRNA-21/phosphoinositide 3-kinase/histone deacetylase 2 axis and NLRP3 inflammasomes, and highlight the potential of these mechanisms as therapeutic targets.

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Section: Introductionmentioning

confidence: 99%

Cellular mechanisms underlying steroid-resistant asthma

et al. 2019

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“…Caspase-1 is activated upon assembly of the nucleotide oligomerization domain–like receptor protein 3 (NLRP3) inflammasome which can be activated, via toll-like receptor 4 (TLR4) by fatty acids. Increased circulating concentrations of lipids are common in obese subjects (89) and also increase after a high-fat meal (90) and increased lung concentrations of fatty acids are also observed in obese mice (91). Moreover, increased sputum concentrations of IL-1β and increased NLRP3 and TLR4 expression in sputum cells are observed in obese versus non obese asthmatic adults (90, 92).…”

Section: Mechanistic Basis For the Role Of Obesity In Severe Asthmamentioning

confidence: 99%

“…Increased circulating concentrations of lipids are common in obese subjects (89) and also increase after a high-fat meal (90) and increased lung concentrations of fatty acids are also observed in obese mice (91). Moreover, increased sputum concentrations of IL-1β and increased NLRP3 and TLR4 expression in sputum cells are observed in obese versus non obese asthmatic adults (90, 92). Eating a meal rich in saturated fatty acids also increases NLRP3 and TLR4 expression in sputum cells (90) and addition of the saturated fatty acid, palmitic acid, to neutrophils and monocytes increases their release of IL-1β when challenged with lipopolysaccharide or TNFα.…”

Section: Mechanistic Basis For the Role Of Obesity In Severe Asthmamentioning

confidence: 99%

“…Moreover, increased sputum concentrations of IL-1β and increased NLRP3 and TLR4 expression in sputum cells are observed in obese versus non obese asthmatic adults (90, 92). Eating a meal rich in saturated fatty acids also increases NLRP3 and TLR4 expression in sputum cells (90) and addition of the saturated fatty acid, palmitic acid, to neutrophils and monocytes increases their release of IL-1β when challenged with lipopolysaccharide or TNFα. Data from mice also indicate a role for the IL-1β/NLRP3 pathway in obese asthma.…”

Section: Mechanistic Basis For the Role Of Obesity In Severe Asthmamentioning

confidence: 99%

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Obesity and severe asthma

Tashiro

Shore

2019

Allergology International

105

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Obesity is an important global health issue for both children and adults. Obesity increases the prevalence and incidence of asthma and also increases the risk for severe asthma. Here we describe the features of severe asthma phenotypes for which obesity is a defining characteristic, including steroid resistance, airway inflammation, and co-morbidities. We also review current concepts regarding the mechanistic basis for the impact of obesity in severe asthma, including possible roles for vitamin D deficiency, systemic inflammation, and the microbiome. Finally, we describe data indicating a role for diet, weight loss, and exercise in the treatment of severe asthma with obesity. Better understanding of the mechanistic basis for the role of obesity in severe asthma could lead to new therapeutic options for this population.

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“…The NLRP3 inflammasome is an intracellular receptor of danger-associated molecular pattern molecules that is activated by host-derived "danger signals," such as extracellular ATP (9), b-amyloid (10), and saturated fatty acids (11). Research indicates that a 2-step process is responsible for activation of the NLRP3 inflammasome (12).…”

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confidence: 99%

Optineurin inhibits NLRP3 inflammasome activation by enhancing mitophagy of renal tubular cells in diabetic nephropathy

Chen

Feng

et al. 2018

FASEB j.

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Tubulointerstitial inflammation plays a critical role in the progression of diabetic nephropathy (DN), and nucleotide‐binding oligomerization domain‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasomes contribute to renal interstitial inflammation in DN. Decreased expression of optineurin (OPTN) is also associated with the progression of DN. We investigated the role of OPTN in activation of the NLRP3 inflammasome in DN. We initially examined the renal biopsy tissues of 172 patients with type 2 DN and 32 nondiabetic patients with renal hamartoma. Expression of renal OPTN was significantly lower in patients with DN and negatively correlated with urinary levels of IL‐1β and IL‐18. Confocal microscopy analysis of the biopsies indicated no NLRP3 or IL‐1β staining in OPTN‐positive renal tubular epithelial cells (RTECs), indicating a negative correlation of OPTN expression with the activation of NLRP3 inflammasome. In vitro studies of murine RTECs indicated the levels of OPTN mRNA and protein decreased significantly after stimulation by a high glucose (HG) treatment. Relative to RTECs given HG., RTECs overexpressing OPTN showed significantly lower levels of NLRP3 expression, cleavage of caspase‐1 and IL‐1β, and release of IL‐1β and IL‐18. Overexpression of OPTN in the presence of HG significantly increased the costaining of microtubule‐associated protein 1A/1B‐Iight chain 3‐II and translocase of outer mitochondrial membrane 20 in RTECs, suggesting that OPTN enhances mitophagy. In addition, mitochondrial division inhibitor 1 blocked the inhibitory effect of OPTN overexpression on the activation of NLRP3 inflammasome in the presence of HG., indicating that OPTN overexpression inhibited NLRP3 inflammasome activation by enhancement of mitophagy. OPTN gene silencing significantly enhanced production of mitochondrial reactive oxygen species (mtROS) in the presence of HG. Compared with HG+OPTN small interfering RNA (siRNA)‐treated RTECs, HG+OPTN siRNA+MitoTempo‐treated RTECs attenuated NLRP3 inflammasome activation, suggesting that OPTN gene silencing activates the NLRP3 inflammasome by increasing mtROS in HG‐treated RTECs. Taken together, our results demonstrate that OPTN inhibits the activation of NLRP3 inflammasome by enhancing mitophagy.—Chen, K., Feng, L., Hu, W., Chen, J., Wang, X., Wang, L., He, Y. Optineurin inhibits NLRP3 inflammasome activation by enhancing mitophagy of renal tubular cells in diabetic nephropathy. FASEB J. 33, 4571–4585 (2019). http://www.fasebj.org

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Saturated fatty acids, obesity, and the nucleotide oligomerization domain–like receptor protein 3 (NLRP3) inflammasome in asthmatic patients

Abstract: The NLRP3 inflammasome is a potential therapeutic target in asthmatic patients. Behavioral interventions that reduce fatty acid exposure, such as weight loss and dietary saturated fat restriction, warrant further exploration.

Cited by 104 publications

References 46 publications

Cellular mechanisms underlying steroid-resistant asthma

Cellular mechanisms underlying steroid-resistant asthma

Obesity and severe asthma

Optineurin inhibits NLRP3 inflammasome activation by enhancing mitophagy of renal tubular cells in diabetic nephropathy

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