NLRP3 Inflammasome as a Potential Therapeutic Target in Dry Eye Disease

Abstract

Dry eye disease (DED) is a multifactorial ocular surface disorder arising from numerous interrelated underlying pathologies that trigger a self-perpetuating cycle of instability, hyperosmolarity, and ocular surface damage. Associated ocular discomfort and visual disturbance contribute negatively to quality of life. Ocular surface inflammation has been increasingly recognised as playing a key role in the pathophysiology of chronic DED. Current readily available anti-inflammatory agents successfully relieve symptoms, but often without addressing the underlying pathophysiological mechanism. The NOD-like receptor protein-3 (NLRP3) inflammasome pathway has recently been implicated as a key driver of ocular surface inflammation, as reported in pre-clinical and clinical studies of DED. This review discusses the intimate relationship between DED and inflammation, highlights the involvement of the inflammasome in the development of DED, describes existing anti-inflammatory therapies and their limitations, and evaluates the potential of the inflammasome in the context of the existing anti-inflammatory therapeutic landscape as a therapeutic target for effective treatment of the disease.

NLRP3 Inflammasome as a Potentially New Therapeutic Target of Mesenchymal Stem Cells and Their Exosomes in the Treatment of Inflammatory Eye Diseases

“…The activation of the NLRP3 inflammasome in eye-infiltrated immune cells leads to the enhanced production of pro-inflammatory cytokines (interleukin-1β (IL-1β) and IL-18), which elicit inflammatory processes in ocular structures [ 10 ].…”

“…The priming step of NLRP3 inflammasome activation is elicited by the activation of pattern recognition receptors (PRRs), including Toll-like receptors (TLR). These membrane-bound receptors are expressed on immune cells where recognized pathogen-associated molecular patterns (PAMPs) of microbial antigens or damage-associated molecular patterns (DAMPs) are released from injured cells [ 10 , 11 ]. Signals generated from activated PRRs, particularly TLR-2, TLR-4, TLR-5, and TLR-6, initiate phosphorylation and the consequent activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK), which, in turn, phosphorylate c-Jun, ATF-2, and CREB transcription factors that bind to the promoter regions of NLRP3 and pro-IL-1β, leading to their transcriptional upregulation [ 10 , 11 ].…”

“…These membrane-bound receptors are expressed on immune cells where recognized pathogen-associated molecular patterns (PAMPs) of microbial antigens or damage-associated molecular patterns (DAMPs) are released from injured cells [ 10 , 11 ]. Signals generated from activated PRRs, particularly TLR-2, TLR-4, TLR-5, and TLR-6, initiate phosphorylation and the consequent activation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK), which, in turn, phosphorylate c-Jun, ATF-2, and CREB transcription factors that bind to the promoter regions of NLRP3 and pro-IL-1β, leading to their transcriptional upregulation [ 10 , 11 ]. Additionally, upon binding to TLRs, TLR ligands elicit the MyD88-driven activation of IL-1R-associated kinase 1 (IRAK-1), which, in a TNFR-associated factor 6 (TRAF6)-dependent manner, induces the activation of transforming growth factor-beta-activated kinase 1 (TAK-1), a key protein kinase responsible for the optimal activation of NF-κB.…”

“…This second step is driven by NLRP3 agonists, which activate NLRP3 to cause inflammasome assembly and mature IL-1 production. It can be triggered by a variety of stimuli, including microbial components, extracellular matrix breakdown products, and environmental antigens [ 10 , 11 , 12 ]. The exact mechanisms by which these stimuli activate the NLRP3 inflammasome are still not fully understood, but proposed mechanisms include alterations in potassium (K + ) efflux, lysosomal rupture, mitochondrial dysfunction, and enhanced reactive oxygen species (ROS) production [ 10 , 11 ].…”

“…It can be triggered by a variety of stimuli, including microbial components, extracellular matrix breakdown products, and environmental antigens [ 10 , 11 , 12 ]. The exact mechanisms by which these stimuli activate the NLRP3 inflammasome are still not fully understood, but proposed mechanisms include alterations in potassium (K + ) efflux, lysosomal rupture, mitochondrial dysfunction, and enhanced reactive oxygen species (ROS) production [ 10 , 11 ]. Increased intracellular levels of ATP, massive accumulation of uric acid crystals, microbial antigens, and environmental irritants can induce potassium (K + ) efflux from the immune cell, leading to decreased intracellular potassium levels.…”