GPR4 is a pH-sensing G protein-coupled receptor highly expressed in vascular endothelial cells and can be activated by protons in the inflamed tissue microenvironment. Herein, we report that acidosisinduced GPR4 activation increases paracellular gap formation and permeability of vascular endothelial cells through the G a12/13 /Rho GTPase signaling pathway. Evaluation of GPR4 in the inflammatory response using the acute hindlimb ischemia-reperfusion mouse model revealed that GPR4 mediates tissue edema, inflammatory exudate formation, endothelial adhesion molecule expression, and leukocyte infiltration in the inflamed tissue. Genetic knockout and pharmacologic inhibition of GPR4 alleviate tissue inflammation. These results suggest GPR4 is a pro-inflammatory receptor and could be targeted for therapeutic intervention.

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.

Neurodegeneration is associated with defects in cytoskeletal dynamics and dysfunctions of the vesicular trafficking and sorting systems. In the last few decades, studies have demonstrated that the key regulators of cytoskeletal dynamics are proteins from the Rho family GTPases, meanwhile, the central hub for vesicle sorting and transport between target membranes is the Rab family of GTPases. In this regard, the role of Rho and Rab GTPases in the induction and maintenance of distinct functional and morphological neuronal domains (such as dendrites and axons) has been extensively studied. Several members belonging to these two families of proteins have been associated with many neurodegenerative disorders ranging from dementia to motor neuron degeneration. In this analysis, we attempt to present a brief review of the potential crosstalk between the Rab and Rho family members in neurodegenerative pathologies such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington disease, and amyotrophic lateral sclerosis (ALS).

BackgroundAlzheimer disease (AD) is histopathologically characterized by brain accumulation of amyloid plaques, neurofibrillary tangle formation, and loss of synapses. The small GTPases of Rho family such as RhoA, Rac1 and Cdc42 play an important role in neural plasticity by regulating synaptic actin and spine dynamics. However, the functions of these proteins in AD are paradoxical. To understand their contributions in AD pathogenesis, it is important to investigate the relationship between the expression of Rho GTPases and their functional states in signaling.MethodWe characterized the spatial dysregulation of Rho GTPases in human AD brains and that of aged Triple Transgenic (3xTg‐AD) mouse model carrying mutations in amyloid precursor protein, tau protein, and presenilin. For human brains, the paraffin‐embedded tissues were collected from age and gender matched AD and Non‐Dementia (ND) patients. Phosphorylated Rho GTPase antibodies were used as signaling indicators for immunofluorescence microscopyResultWe observed altered phospho‐RhoA (S188) and phospho‐Rac/Cdc42(S71) expression and distribution in human, wild type (WT), and 3xTg‐AD mouse brains. In the CA3 region and dentate gyrus (DG), pRac/Cdc42 immunostaining showed decreased punctate staining in WT compared to 3xTg‐AD mice. For CA3 pRhoA immunostaining scored a slightly higher level of expression in WT compared to 3xTg‐AD. In the CA2 region, pRac/Cdc42 immunostaining was perinuclear in WT and diffused in 3xTg‐AD, whereas the pRhoA immunostaining pattern was similar between WT and 3xTg‐AD. In the CA1 region, pRac/Cdc42 immunostaining showed perinuclear as well as dendritic localization in WT and 3xTg‐AD, while pRhoA immunostaining between WT and 3xTg‐AD was similar. In human brains,there was no significant difference in pRhoA in cortex between ND and AD whereas pRac/Cdc42 was slightly reduced in AD cortex. However, while Rac signaling was reduced, Cdc42 signaling was increased in ND compared to AD cortex. On the other hand, Rac signaling is decreased in ND DG compared to AD whereas the differences in Cdc42 signaling in DG were not significant.ConclusionSmall GTPases of Rho family are differentially dysregulated in expression, distribution, and functional states in different areas of the brain in AD patients as well as in AD mouse brains