Heterotrimeric G Protein Signaling In Allergic Inflammation

National Institute Of Allergy And Infectious Diseases

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Abstract

Mast cells (MCs), granulocytes, and lymphocytes are central to the development of allergic responses. In addition, allergic inflammation can be initiated through activation of receptors coupled to heterotrimeric G proteins (GPCRs). The goal of this study is to understand the mechanisms of G protein–mediated signaling in immune cells, with a particular focus on GPCR-driven leukocyte trafficking to sites of allergic inflammation. GPCRs activate a core pathway involving heterotrimeric G proteins. The Gα subunit cycles between an inactive GDP-bound state and an active GTP-bound state, depending on ligand occupancy of the receptor. In its GTP-bound form, the Gα subunit initiates downstream signaling cascades, including intracellular calcium flux, which in turn drives mast cell and basophil degranulation. This project focuses on a family of regulators of G protein signaling (RGS proteins). RGS proteins inhibit the activity of Gαi and Gαq, but not Gαs, by accelerating their intrinsic GTPase activity. This GTPase-accelerating (GAP) function promotes timely deactivation of the signaling pathway, effectively limiting the duration of active Gα–effector interactions and desensitizing GPCR signaling. While much is known about the biochemical mechanisms of RGS proteins, their physiological roles in allergic inflammation remain less clear. A major area of investigation is the recruitment of inflammatory leukocytes to sites of allergic inflammation. Chemokines, acting through leukocyte GPCRs, are key mediators of immune cell trafficking. RGS proteins such as RGS10, RGS13, and RGS16 limit chemokine signaling by promoting GPCR desensitization. Mouse genetic studies reveal that RGS proteins play distinct roles in airway hyperresponsiveness (AHR): Rgs2 or Rgs5 deletion enhances AHR and airway smooth muscle contraction. In contrast, Rgs4 knockout (KO) mice unexpectedly show decreased AHR due to increased production of the bronchodilator prostaglandin E2 (PGE2) by lung epithelial cells. In FY25, we further examined mice carrying an Rgs4 point mutation (N128A), which severely reduces GAP activity. These knock-in mice exhibited increased AHR, reduced airway PGE2 levels, and enhanced GPCR-induced bronchoconstriction compared with either Rgs4 KO or wild-type controls. Mechanistically, RGS4 was found to interact with the p85α subunit of PI3K and suppress PI3K-dependent PGE2 secretion induced by transforming growth factor beta (TGF-β) in airway epithelial cells. Together, these findings suggest that RGS4 influences asthma severity not only by regulating G protein–dependent signaling but also through a G protein–independent mechanism, specifically modulation of epithelial PI3K–PGE2 pathways that shape the inflammatory milieu of the airway.