P2X7 receptor mediates NLRP3 inflammasome activation in depression and diabetes

Abstract

The increasing prevalence of depression and diabetes mellitus has become a major public health problem worldwide. Studies have shown that people with diabetes are at a high risk of being diagnosed with depression, and diabetes complicates depression treatment by promoting the deterioration of glycemic control, reducing self-care ability and quality of life, and causing severe functional disability and early mortality. Moreover, health deterioration dramatically increases the financial cost of social and health care system. Thus, how to treat depression, diabetes, and diabetes complicated by depression has become one of the world's urgent concerns. The activation of nod-like receptor family pyrin domain containing 3 (NLRP3) is closely related to mental illness. This finding provides a new perspective for studying depression. NLRP3 plays an important role in the development of diabetes. In this review, we elaborate the definition and epidemiology of depression, diabetes, and diabetic depression and introduce the functional characteristics of an NLRP3 inflammasome and upstream P2X7 receptor. Moreover, related research on NLRP3 inflammasomes and P2X7 receptors is summarized and used as a reference for confirming that the excessive activation of P2X7- NLRP3 leads to the increased release of inflammatory cytokines, such as IL-1β, in depression and diabetes. We provide insights into the P2X7-NLRP3-IL-1β pathway as an important pathological mechanism and novel therapeutic target in diabetes and depression. Given that the P2X7-NLRP3-IL-1β pathway may play an important role in diabetes confounded by comorbid depression, the possibility of intervention with baicalin is proposed.

Keywords: Baicalin; Depression; Diabetes mellitus; Diabetes mellitus with depression; Inflammatory; NLRP3 inflammasome; P2X7 receptor.

Fig. 1

Pathological mechanism of depression induced by the P2X7–NLRP3–IL-1β pathway. Stress stimulates the production and release of excessive Glu at the synaptic terminals of neurons, promoting astrocytes to release a large amount of ATP. In the microglia, P2X7 receptors are activated by excessive extracellular ATP levels, which lead to cascade reactions and induce the overactivation of NLRP3 inflammasomes. Activated caspase-1 induces the maturation and release of IL-1β, which triggers neuroinflammation that can lead to depression

Fig. 2

Pathological mechanism of DM induced by the P2X7–NLRP3–IL-1β pathway. Chronic hyperglycemia stimulates the activation of the P2X7–NLRP3 inflammasome, resulting in the excessive release of proinflammatory factor IL-1β. By inducing pancreatic β cell dysfunction and death, IL-1β can reduce insulin secretion, impair the insulin signal pathway, and aggravate hyperglycemia. In addition, IL-1β accelerates the development of insulin resistance, and with the decrease of insulin sensitivity, the cellular uptake and utilization of glucose are reduced, hyperglycemia is further aggravated, and diabetes is finally induced

Fig. 3

Pathological mechanism of DD induced by the P2X7–NLRP3–IL-1β pathway. The activation of P2X7-NLRP3 inflammasome leads to systemic immune responses, inducing depression and diabetes. NLRP3-dependent IL-1β may lead to insulin resistance and impaired insulin signal in depressed patients, thus promoting the occurrence of diabetes. Moreover, the P2X7–NLRP3–IL-1β pathway aggravates metabolic imbalance and triggers the neuroinflammation of the central nervous system, rendering diabetic patients prone to comorbid depression