GRK2 selectively attenuates the neutrophil NADPH-oxidase response triggered by β-arrestin recruiting GPR84 agonists

Fredriksson, Johanna; Holdfeldt, André; Mårtensson, Jonas; Björkman, Lena; Møller, Thor C.; Müllers, Erik; Dahlgren, Cláes; Sundqvist, Martina; Forsman, Huamei

doi:10.1016/j.bbamcr.2022.119262

Cited by 9 publications

(19 citation statements)

References 59 publications

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“…Furthermore, this study also showed that neutrophils pre-treated with GRK2 inhibitors display (i) an enhanced GPR84-mediated ROS production and (ii) a reduced GPR84-mediated β-arrestin recruitment, whereas (iii) the receptor downstream PLC-PIP 2 -IP 3 -Ca 2+ signalling pathway was unaffected. These results thus highlight a role of GRK2 in regulating GPR84 signalling that may be specific for this receptor, as the same responses, when mediated through FPR2, were unaffected by GRK2 inhibition (Fredriksson et al, 2022). At the mechanistic level, it is reasonable to assume that the difference in the potential phosphorylation sites between GPR84 and FPR2 may determine the effects of GRK2 inhibition.…”

Section: Regulation Of Gpr84 By Intracellular Signalling Moleculesmentioning

confidence: 66%

Function and regulation of GPR84 in human neutrophils

Forsman

Dahlgren

Mårtensson

et al. 2023

British J Pharmacology

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Human neutrophils are components of the innate immune system and are the most abundant white blood cells in the circulation. They are professional phagocytes and express several G protein‐coupled receptors (GPCRs), which are essential for proper neutrophil functions. So far, the two formyl peptide receptors, FPR1 and FPR2, have been the most extensively studied group of neutrophil GPCRs, but recently, a new group, the free fatty acid (FFA) receptors, has attracted growing attention. Neutrophils express two FFA receptors, GPR84 and FFA2, which sense medium‐ and short‐chain fatty acids respectively, and display similar activation profiles. The exact pathophysiological role of GPR84 is not yet fully understood, but it is generally regarded as a pro‐inflammatory receptor that mediates neutrophil activation. In this review, we summarize current knowledge of how GPR84 affects human neutrophil functions and discuss the regulatory mechanisms that control these responses, focusing on the similarities and differences in comparison to the two FPRs and FFA2.

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Section: Regulation Of Gpr84 By Intracellular Signalling Moleculesmentioning

confidence: 66%

Function and regulation of GPR84 in human neutrophils

Forsman

Dahlgren

Mårtensson

et al. 2023

British J Pharmacology

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“…Such effects probably reflect the contribution of GRK2 family kinases, because 2-HTP-dependent phosphorylation was markedly impaired in cells by pre-treatment with the GRK2/GRK3 inhibitor cmpd 101 (Marsango et al, 2022). A key role of GRK2 family kinases in the regulation of GPR84 in human neutrophils has been reported based on similar inhibitor studies (Fredriksson et al, 2022).…”

Section: Arrestin Proteins Regulate Gpr84 Desensitisation and Interna...mentioning

confidence: 67%

Regulation of the pro‐inflammatory G protein‐coupled receptor GPR84

Marsango

Milligan

2023

British J Pharmacology

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GPR84 is an understudied rhodopsin‐like class A G protein‐coupled receptor, which is arousing particular interest from a therapeutic perspective. Not least this reflects that gpr84 expression is significantly up‐regulated following acute inflammatory stimuli and in inflammatory diseases, and that receptor activation plays a role in regulating pro‐inflammatory responses and migration of cells of the innate immune system such as neutrophils, monocytes, macrophages and microglia. Although most physiological responses of GPR84 reflect receptor coupling to Gαi/o‐proteins, several studies indicate that agonist‐activated GPR84 can recruit arrestin adaptor proteins and this regulates receptor internalisation and desensitisation. To date, little is known on the patterns of either basal or ligand regulated GPR84 phosphorylation and how these might control these processes. Here, we consider what is known about the regulation of GPR84 signalling with a focus on how G protein receptor kinase‐mediated phosphorylation regulates arrestin protein recruitment and receptor function.

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“…120 By the use of GRK2 specific inhibitors, this kinase has been shown to be present in the neutrophil cytosol and to be part of the system that regulates GPR84 signaling. 121 No effect was induced by the inhibitors on FPR2 signaling, suggesting that the effect was receptor specific. In addition, and in agreement with the coupling to β-arrestin, the GRK2 inhibitors had no effect on the response induced by a biased non β-arrestin recruiting GPR84 agonist.…”

Section: The Neutrophil Gpr84mentioning

confidence: 99%

“…Arrestin binding is promoted by the receptor phosphorylation mediated by GRK, a process that directs receptor function away from G protein signaling to desensitization/internalization 120 . By the use of GRK2 specific inhibitors, this kinase has been shown to be present in the neutrophil cytosol and to be part of the system that regulates GPR84 signaling 121 . No effect was induced by the inhibitors on FPR2 signaling, suggesting that the effect was receptor specific.…”

Section: Defined Neutrophil Gpcrsmentioning

confidence: 99%

G protein coupled pattern recognition receptors expressed in neutrophils: Recognition, activation/modulation, signaling and receptor regulated functions

Dahlgren

Lind

Mårtensson

et al. 2022

Immunological Reviews

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Summary Neutrophils, the most abundant white blood cell in human blood, express receptors that recognize damage/microbial associated pattern molecules of importance for cell recruitment to sites of inflammation. Many of these receptors belong to the family of G protein coupled receptors (GPCRs). These receptor‐proteins span the plasma membrane in expressing cells seven times and the down‐stream signaling rely in most cases on an activation of heterotrimeric G proteins. The GPCRs expressed in neutrophils recognize a number of structurally diverse ligands (activating agonists, allosteric modulators, and inhibiting antagonists) and share significant sequence homologies. Studies of receptor structure and function have during the last 40 years generated important information on GPCR biology in general; this knowledge aids in the overall understanding of general pharmacological principles, governing regulation of neutrophil function and inflammatory processes, including novel leukocyte receptor activities related to ligand recognition, biased/functional selective signaling, allosteric modulation, desensitization, and reactivation mechanisms as well as communication (receptor transactivation/cross‐talk) between GPCRs. This review summarizes the recent discoveries and pharmacological hallmarks with focus on some of the neutrophil expressed pattern recognition GPCRs. In addition, unmet challenges, including recognition by the receptors of diverse ligands and how biased signaling mediate different biological effects are described/discussed.

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GRK2 selectively attenuates the neutrophil NADPH-oxidase response triggered by β-arrestin recruiting GPR84 agonists

Cited by 9 publications

References 59 publications

Function and regulation of GPR84 in human neutrophils

Function and regulation of GPR84 in human neutrophils

Regulation of the pro‐inflammatory G protein‐coupled receptor GPR84

G protein coupled pattern recognition receptors expressed in neutrophils: Recognition, activation/modulation, signaling and receptor regulated functions

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