Dysregulation of the NLRP3 Inflammasome in Diabetic Retinopathy and Potential Therapeutic Targets

Abstract

Diabetic Retinopathy (DR) is an insidious neurovascular disorder secondary to chronic glycemic dysregulation in elderly diabetic patients. In the later stages of DR, the disease manifests as fluid infiltrating the macula, culminating in the leading cause of irreversible visual impairment in working age adults. With the current mainstay treatments preoccupied with slowing down the progression of DR, this presents an unsustainable solution from both an economic and quality of life perspective. Although the exact mechanisms by which hyperglycemia leads to retinal tissue insult are unknown, the evidence suggests that chronic low-grade inflammation in diabetic eye is in part driving the constellation of symptoms present in DR. Of the innate immune system within the eye, the NLR Family Pyrin Domain Containing 3 Inflammasome (NLRP3) has been identified in retinal cells as a causal factor in the pathogenesis of DR. Multiple pathways appear to be present in the diabetic eye that instigate prolonged activation of the NLRP3 which subsequently exerts its deleterious effects by upregulating the release of Interleukin-1Beta and Interleukin-18. In this review, we highlight the current understanding of the pathophysiology of DR, the dysregulation of the NLRP3 secondary to hyperglycemic stress in retinal cells, and novel therapeutic targets to alleviate overactivation of the inflammasome.

Vascular Inflammation in Lungs of Patients with Fatal Coronavirus Disease 2019 (COVID-19) Infection: Possible role for the NLRP3 inflammasome

“…Inflammatory processes involve the participation of inflammasomes that are multimeric platforms assembled in response to pathogenic stimuli. Dysregulated inflammasome signaling has been well established as a pivotal event in hyper-inflammatory syndromes (25, 33, 37). Among the inflammasomes, the NLRP3 inflammasome comprising of the NLRP3 subunit, ASC and caspase-1, is well established to be activated in response to microbial infection (2, 29) and to drive cell death (3, 31).…”

NLRP3 Inflammasome: A Potential Target in Isoflurane Pretreatment Alleviates Stroke-Induced Retinal Injury in Diabetes

“…The robust inflammatory response is an important contributor to the progression of cerebral ischemia, retinal ischemia, and diabetic retinopathy (Anrather and Iadecola, 2016 ; Capitao and Soares, 2016 ; Mathew et al, 2019 ; Yang et al, 2020 ). The NLRP3 inflammasome, a multimeric protein complex and critical component of the inflammatory response, has been linked to the pathogenesis of all three conditions (Hong et al, 2018 ; Raman and Matsubara, 2020 ; Yu et al, 2020 ). Upon recruitment to the inflammasome, caspase-1 is activated, leading to the release of proinflammatory IL-1β and IL-18, and triggering an infiltration of immune cells and intrinsic cell death mechanisms (Yu et al, 2020 ).…”

Lychee seed polyphenol protects blood–retinal barrier by increasing tight joint proteins and inhibiting the activation of TLR4/MYD88/NF-κB-mediated NLRP3 inflammasome

“…Among them, the inflammatory responses in Müller cells result in the change in the morphology of endothelial cells and BRB injury. The damaged BRB with destructed structure and increased permeability is an important pathological hallmark of DR (Raman & Matsubara, 2020). With the development of diabetes, the risk of retinal ischemia and hypoxia increases, which is accompanied by the progressive destroyed BRB structure and function, as well as increased capillary permeability, thickened basement membrane and capillary occlusion.…”