Targeting the NLRP3 inflammasome-IL-1β pathway in type 2 diabetes and obesity

Abstract

Increased activity of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome-IL-1β pathway is observed in obesity and contributes to the development of type 2 diabetes and its complications. In this review, we describe the pathological activation of IL-1β by metabolic stress, ageing and the microbiome and present data on the role of IL-1β in metabolism. We explore the physiological role of the IL-1β pathway in insulin secretion and the relationship between circulating levels of IL-1β and the development of diabetes and associated diseases. We highlight the paradoxical nature of IL-1β as both a friend and a foe in glucose regulation and provide details on clinical translation, including the glucose-lowering effects of IL-1 antagonism and its impact on disease modification. We also discuss the potential role of IL-1β in obesity, Alzheimer's disease, fatigue, gonadal dysfunction and related disorders such as rheumatoid arthritis and gout. Finally, we address the safety of NLRP3 inhibition and IL-1 antagonists and the prospect of using this therapeutic approach for the treatment of type 2 diabetes and its comorbidities.

Keywords: Clinical study; Diabetes; IL-1β; Inflammasome; Inflammation; Insulin; NLRP3; Obesity; Pancreatic islet; Review.

Fig. 1

Schematic overview of canonical IL-1β production and secretion. TLR2, TLR4 and IL-1 signalling prime myeloid cells, starting the transcription of inflammasome components (e.g. PYCARD [ASC], NLRP3) and IL-1-responsive genes (e.g. IL1B, IL1RN [IL-1RA], CXCL8 [IL-8], IL6). Glucose, K⁺ efflux, and DAMPs and PAMPs trigger intracellular stimuli that act as a second signal activating the NLRP3 inflammasome. Elevated cytosolic levels of reactive oxygen species (ROS), islet amyloid polypeptide (IAPP) and ATP activate NLRP3 receptors. ROS and crystalline substances such as cholesterol and uric acid disrupt the lysosomal membrane in phagocytes, promoting leakage of lysosome cargo into the cytosol, releasing epitopes that are recognised by the LRR domain of the NLRP3 receptor. The NLRP3 inflammasome is composed of the sensor NLRP3, the adaptor protein ASC and the effector molecule caspase-1. On receiving a second stimulus, the NLRP3 inflammasome is assembled in the cytosol, leading to the activation of caspase-1 and subsequent secretion of active IL-1β via the gasdermin D pore. After being secreted, IL-1β binds to the IL-1R1, amplifying intracellular inflammatory signalling and transcription of NLRP3 inflammasome components. TCA, tricarboxylic acid. This figure is available as part of a downloadable slideset

Fig. 2

Role of the NLRP3 inflammasome–IL-1β pathway in the pathogenesis of metabolic diseases and comorbidities. Metabolic stress induced by NEFAs, glucose, cholesterol, uric acid and islet amyloid polypeptide (IAPP), along with ageing and changes in the microbiome, activate NLRP3 with subsequent cleavage of pro-IL-1β. In turn, IL-1β contributes to impaired insulin secretion, insulin resistance, MAFLD, atherosclerosis, heart failure, retinopathy, nephropathy, neuropathy, obesity, Alzheimer’s disease, fatigue, testosterone deficiency, polycystic ovary syndrome, rheumatoid arthritis and gout. Blocking IL-1 signalling or inhibition of NLRP3 counteracts pathologies associated with metabolic diseases. This figure is available as part of a downloadable slideset