Role of G protein-coupled receptors in inflammation

Abstract

G protein-coupled receptors (GPCRs) play important roles in inflammation. Inflammatory cells such as polymorphonuclear leukocytes (PMN), monocytes and macrophages express a large number of GPCRs for classic chemoattractants and chemokines. These receptors are critical to the migration of phagocytes and their accumulation at sites of inflammation, where these cells can exacerbate inflammation but also contribute to its resolution. Besides chemoattractant GPCRs, protease activated receptors (PARs) such as PAR1 are involved in the regulation of vascular endothelial permeability. Prostaglandin receptors play different roles in inflammatory cell activation, and can mediate both proinflammatory and anti-inflammatory functions. Many GPCRs present in inflammatory cells also mediate transcription factor activation, resulting in the synthesis and secretion of inflammatory factors and, in some cases, molecules that suppress inflammation. An understanding of the signaling paradigms of GPCRs in inflammatory cells is likely to facilitate translational research and development of improved anti-inflammatory therapies.

Figure 1

Signaling pathways of GPCRs involved in inflammation. Signaling by GPCRs is initiated by a specific ligand that binds and activates the receptor inducing conformational changes in the receptor. A partial list of the relevant ligands is given in the top panel. All 4 classes of G proteins are involved in the regulation of events that lead to inflammatory cell activation or inactivation. Major effectors, including second messengers and other signaling molecules involved in the regulation of inflammation are shown. These include Ca²⁺, cAMP, protein kinases, lipid kinases, lipases, phosphoinositides, small GTPases and the relevant guanine nucleotide exchange factors, and transcriptional factors. The final output is manifested as nuclear, cytoplasmic and extracellular activities such as expression of proinflammatory genes, production of oxidants, and generation of tissue damaging and repairing factors.