Toll-like receptors, the NLRP3 inflammasome, and interleukin-1β in the development and progression of type 1 diabetes

Abstract

Traditionally, type 1 diabetes (T1D) has been thought of as a disease of cellular immunity, but there is increasing evidence that components of the innate immune system, controlled largely by Toll-like receptors (TLRs), play a significant role in T1D development. TLRs are pattern-recognition molecules on immune cells that recognize pathogens, leading to the production of cytokines such as interleukin-1β (IL1β, encoded by the IL1B gene). IL1β is increased in patients with newly diagnosed T1D and likely acts as an early inflammatory signal in T1D development. Because hyperglycemia is a hallmark of T1D, the effects of hyperglycemia on IL1β expression in peripheral blood mononuclear cells (PBMcs) and islet cells have been examined, but with inconsistent results, and the mechanisms leading to this increase remain unknown. Fatty acids stimulate IL1β expression and may promote inflammation, causing hyperglycemia and insulin resistance. The mechanisms by which IL1β is involved in T1D pathogenesis are controversial. Overall, studies in pancreatic β-cells suggest that IL1β-mediated damage to islet cells involves multiple downstream targets. Potential therapies to decrease the progression of T1D based on IL1β biology include pioglitazone, glyburide, IL1 receptor antagonists, and agents that remove IL1β from the circulation.

Exogenous Hydrogen Sulfide Attenuates High Glucose-Induced Cardiotoxicity by Inhibiting NLRP3 Inflammasome Activation by Suppressing TLR4/NF-κB Pathway in H9c2 Cells

“…Similarly, in another study of monocytes, siRNA knockdown of TLR4 led to decreased NF-κB activity and IL-1β release [41]. Moreover, NF-κB has been reported to enhance the expression of NLRP3 and IL-1β, and NF-κB sites in NLRP3 promoter have been identified [10,42,43]. And third, NF-κB increases the amount of thioredoxin interacting protein and oxidized mitochondrial DNA, which might serve as ligands of NLRP3 [44,45].…”

The Role of Exogenous Hydrogen Sulfide in Free Fatty Acids Induced Inflammation in Macrophages

“…Furthermore, siRNA mediated silencing of TLR4 in monocytes led to decreased NF-κB activity and IL-1β release [35]. Moreover, NF-κB is known to increase expression of NLRP3 and IL-1β; in fact NF-κB binding sites are present in the NLRP3 promoter [36, 37]. Cumulatively, NLRP3 inflammasome activation is thus a central outcome of TLR4/NF-κB stimulation in FFA-overload-mediated inflammation.…”

Protective Action of Anandamide and Its COX-2 Metabolite against L-Homocysteine-Induced NLRP3 Inflammasome Activation and Injury in Podocytes

“…Recent evidence suggests that aberrant activation of NLRP3 inflammasome, an intracellular inflammatory machinery, is involved in the development of different chronic degenerative diseases and pathologic processes. Examples include diabetes mellitus (Masters et al, 2010;Grishman et al, 2012;Lee et al, 2013), obesity (Esser et al, 2013;Wang et al, 2014), silicosis (Peeters et al, 2013;Peeters et al, 2014), liver cirrhosis (Wree et al, 2014), and ESRD (Abais et al, 2014a, b;Xia et al, 2014). The latter group of studies by our laboratory demonstrate that the formation and activation of the NLRP3 inflammasome contributes to glomerular injury from a sterile inflammatory response to hHcys.…”