Can GPR4 Be a Potential Therapeutic Target for COVID-19?

Abstract

Coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first emerged in late 2019 and has since rapidly become a global pandemic. SARS-CoV-2 infection causes damages to the lung and other organs. The clinical manifestations of COVID-19 range widely from asymptomatic infection, mild respiratory illness to severe pneumonia with respiratory failure and death. Autopsy studies demonstrate that diffuse alveolar damage, inflammatory cell infiltration, edema, proteinaceous exudates, and vascular thromboembolism in the lung as well as extrapulmonary injuries in other organs represent key pathological findings. Herein, we hypothesize that GPR4 plays an integral role in COVID-19 pathophysiology and is a potential therapeutic target for the treatment of COVID-19. GPR4 is a pro-inflammatory G protein-coupled receptor (GPCR) highly expressed in vascular endothelial cells and serves as a “gatekeeper” to regulate endothelium-blood cell interaction and leukocyte infiltration. GPR4 also regulates vascular permeability and tissue edema under inflammatory conditions. Therefore, we hypothesize that GPR4 antagonism can potentially be exploited to mitigate the hyper-inflammatory response, vessel hyper-permeability, pulmonary edema, exudate formation, vascular thromboembolism and tissue injury associated with COVID-19.

GPR4 knockout attenuates intestinal inflammation and forestalls the development of colitis-associated colorectal cancer in murine models

“…In this study we demonstrate that GPR4-driven intestinal inflammation can increase the development of colorectal tumorigenesis in a colitis-associated colorectal cancer mouse model. Our observations are in line with previous reports establishing a proinflammatory role for GPR4 in several systems such as the brain, heart, kidney, lung, bone, skin, and the gastrointestinal tract [16,18,19,20,33,43,44,45,46,47,48,49]. In addition, GPR4 has a protumorigenic role in hepatocellular, head and neck, breast and colorectal cancers [27,28,29].…”

“…in several systems such as the brain, heart, kidney, lung, bone, skin, and the gastrointestinal tract [16,18,19,20,33,43,44,45,46,47,48,49]. In addition, GPR4 has a protumorigenic role in hepatocellular, head and neck, breast and colorectal cancers [27,28,29].…”

Circulating pyruvate is a potent prognostic marker for critical COVID-19 outcomes

“…GPCRs are the largest family of cell surface receptors and serve as pharmacological targets of ~34% of all FDA-approved drugs ( 41 ). In this context, Yang and colleagues hypothesized that GPR4, a pro-inflammatory receptor, may be implicated in the pathophysiology of COVID-19 and could be a potential therapeutic target to improve COVID-19-related complications ( 46 ). Although other intermediates of the Krebs cycle cannot be excluded, our present results in the context of signaling networks make lactate, succinate and α-ketoglutarate potential targets for the management of COVID-19 complications.…”

The protective effects of NE 52‐QQ57 against interleukin‐33‐induced inflammatory response in activated synovial mast cells

“…[25][26][27] Pharmacological blockage of GPR4 improves inflammatory diseases and lessens edema in inflammatory disorders like arthritis. [14,28] NE 52-QQ57 is a selective, orally administered GPR4 antagonist. Its antagonism of GPR4 may remarkably inhibit the AGE-caused increased expression of important inflammatory cytokines, which mainly cause synovial inflammation in RA.…”

“…Pharmacological inhibition of GPR4 decreases leukocyte infiltration, lessens inflammatory responses, and diminishes tissue edema in many disease models, inclusive of inflammatory bowel disease, ischemic diseases, and chronic obstructive pulmonary disease. [ 14 ] Accumulating evidence suggests that GPR4 could act as an inflammatory mediator in a variety of cells. [ 15 ] Particularly, GPR4 is expressed in cartilage tissue and chondrocytes.…”