Endoplasmic reticulum stress is sufficient for the induction of IL-1β production via activation of the NF-κB and inflammasome pathways

Abstract

The mechanisms underlying pathophysiological states such as metabolic syndrome and obesity include endoplasmic reticulum (ER) stress and aberrant inflammatory responses. ER stress results from the accumulation of misfolded proteins during stress conditions. However, the precise mechanisms by which ER stress modulates inflammation remain incompletely understood. In this study, we hypothesized that ER stress alone could represent a sufficient signal for the modulation of inflammasome-dependent cytokine responses. We found that several ER stress-inducing chemicals and the free fatty acid palmitate can trigger IL-1β secretion in various cell types, including monocytic leukemia cells, primary macrophages and differentiated adipocytes. We show that ER stress primes cells for the expression of pro-IL-1β via NF-κB activation and promotes IL-1β secretion. Enhanced IL-1β secretion depended on the activation of the NLRP3 inflammasome through a mechanism involving reactive oxygen species formation and activation of thioredoxin-interacting protein. Chemical chaperone treatment and the pharmacological application of carbon monoxide inhibited IL-1β secretion in response to ER stress. Our results provide a mechanistic link between ER stress and the regulation of inflammation, and suggest that modulation of ER stress may provide a therapeutic opportunity to block progression of low grade chronic inflammation to metabolic syndrome.

Silver Nanoparticles Induce Degradation of the Endoplasmic Reticulum Stress Sensor Activating Transcription Factor-6 Leading to Activation of the NLRP-3 Inflammasome

“…Our results are in agreement with others reporting that inhibition of S2P was more efficient than S1P to block processing of ATF-6 (38,39). Interestingly, a recent study demonstrated that the classical ER stressor, tunicamycin, is sufficient for the induction of IL-1␤, suggesting a possible link between ER stress and the inflammasome (40). Moreover, tunicamycin was previously shown to induce ATF-6 degradation (7).…”

Innate immunity in diabetes and diabetic nephropathy

“…In addition to TLRs, endoplasmic reticulum stress is known to activate the NLRP3 inflammasome and induce apoptosis in pancreatic β cells 91,92 . This scenario has also been demonstrated in macrophages 93 and adipocytes 94 , and endoplasmic reticulum stress is sufficient for the production of IL1β via the activation of NFκB and the NLRP3 inflammasome.…”

“…The activation of NLRP3 has an important role in the production of IL1 in T2DM and it may be an important target for disease treatment 107,108 . Various factors induce the NLRP3-IL1 pathway, including: islet amyloid polypeptide deposition in the pancreas 100 ; cholesterol crystals in atherosclerotic lesions 109 ; Kilham rat virus in the spleen and lymph nodes of a LEW1.WR1 model of T1DM 110 ; endoplasmic reticulum stress-inducing chemicals and free fatty acid palmitate in macrophages 94 ; FFAs in atherosclerosis lesions 109 and adipose tissues 111 ; extracellular deposition of ATP and P2X4 receptors in kidney 112 ; TLR2/6 and TRL4 ligands in pancreatic islets and macrophages 113 ; and IL22 in CD4 + T cells 114 . In turn, various agents may block and suppress the amplification loop of NLRP3-IL1, such as α1-antitrypsin 115 , losartan (angiotensin receptor blockers) 116 , procyanidin B2, 117 and FOXO1 inhibitor 118 as shown in macrophages.…”

Endoplasmic Reticulum Stress–Induced IRE1α Activation Mediates Cross-Talk of GSK-3β and XBP-1 To Regulate Inflammatory Cytokine Production

“…Moreover, activation of NF-kB and expression of the proinflammatory cytokines have been observed in the liver of mice challenged with the pharmacologic ER stress inducer TM (23).…”