Relevance of NLRP3 Inflammasome-Related Pathways in the Pathology of Diabetic Wound Healing and Possible Therapeutic Targets

Abstract

Wound healing is a major secondary complication in type 2 diabetes, which results in significant disability and mortality, imposing a significant clinical and social burden. Sustained activation of the Nod-like receptor protein (NLRP) inflammasome in wounds is responsible for excessive inflammatory responses and aggravates wound damage. The activation of the NLRP3 inflammasome is regulated by a two-step process: the priming/licensing (signal 1) step involved in transcription and posttranslation and the protein complex assembly (signal 2) step triggered by danger molecules. This review focuses on the advances made in understanding the pathophysiological mechanisms underlying wound healing in the diabetic microenvironment. Simultaneously, this review summarizes the molecular mechanisms of the main regulatory pathways associated with signal 1 and signal 2, which trigger the NLRP3 inflammasome complex assembly in the development of diabetic wounds (DW). Activation of the NLRP3 inflammasome-related pathway, involving the disturbance in Nrf2 and the NF-κB/NLRP3 inflammasome, TLR receptor-mediated activation of the NF-κB/NLRP3 inflammasome, and various stimuli inducing NLRP3 inflammasome assembly play a pivotal role in DW healing. Furthermore, therapeutics targeting the NLRP3 inflammasome-related pathways may promote angiogenesis, reprogram immune cells, and improve DW healing.

Role of NLRP3 in the pathogenesis and treatment of gout arthritis

“…The NLRP3 inflammasome is made up of a sensor, NLRP3 protein, ASC adaptor protein and pro-caspase-1, which can be significantly activated by extracellular adenosine triphosphate (ATP), certain bacterial toxins, mitochondrial damage, and various types of crystalline and particulate matter ( 28 ). Mechanistically, the NLRP3 inflammasome activation is a two-step process that requires initiation and activation signals from a variety of exogenous and endogenous activators ( 29 ). To begin, the priming signal, which is triggered by various pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), effectively promotes the transcriptional activation of NLRP3 inflammasome-containing genes such as NLRP3, pro-IL-1β, and pro-IL-18 in a TLR4/NF-κB pathway dependent manner ( 30 ).…”

Macrophages in Skin Wounds: Functions and Therapeutic Potential

“…The detrimental effects of exacerbated IL-1β signalling in delayed wound healing were further supported by clinical and preclinical observations of diabetic chronic wounds. Chronic wounds from diabetic patients and db/db mice showed the overproduction of IL-1β in macrophages [ 119 , 120 ]. Anti-IL1β-antibody-treated and Il-1r1 −/− diabetic skin wounds showed accelerated wound closure, and resulted in improved collagen deposition, IGF-1 and TGF-β production, and reduced IL-1β and TNF expression ( Table 3 ) [ 119 , 120 ].…”

“…Chronic wounds from diabetic patients and db/db mice showed the overproduction of IL-1β in macrophages [ 119 , 120 ]. Anti-IL1β-antibody-treated and Il-1r1 −/− diabetic skin wounds showed accelerated wound closure, and resulted in improved collagen deposition, IGF-1 and TGF-β production, and reduced IL-1β and TNF expression ( Table 3 ) [ 119 , 120 ]. Similarly, the topical delivery of IL-1ra enhanced neutrophil clearance and macrophage recruitment in diabetic wounds, promoting a pro-healing microenvironment for wound repair ( Table 3 ) [ 119 ].…”

Spatiotemporal On–Off Immunomodulatory Hydrogel Targeting NLRP3 Inflammasome for the Treatment of Biofilm‐Infected Diabetic Wounds

“…Hyperglycemia‐induced abnormal stimulation of the Nod‐like receptor protein 3 (NLRP3) inflammasome in macrophages is a major cause of chronic inflammation in uninfected diabetic wounds. [ 6 ] The NLRP3 activation then promotes macrophage M1 polarization and the formation of neutrophil extracellular traps (NETs), leading to extensive inflammatory infiltration. [ 7 ] Downmodulation of macrophage‐related immune response by targeting NLRP3 has been shown in recent years to accelerate aseptic diabetic wound healing.…”