Roles of Mast Cell G Protein-Coupled Receptor Kinase 2 (GRK2) in Allergy and Inflammation / Monica Thapaliya.

Format:

Book

Thesis/Dissertation

Author/Creator:

Thapaliya, Monica, author.

Contributor:

University of Pennsylvania. Pharmacology, degree granting institution.

Language:

English

Subjects (All):

Immunology.

Pharmacology.

Cellular biology.

Pharmacology--Penn dissertations.

Penn dissertations--Pharmacology.

Local Subjects:

Immunology.

Pharmacology.

Cellular biology.

Pharmacology--Penn dissertations.

Penn dissertations--Pharmacology.

Physical Description:

1 online resource (107 pages)

Contained In:

Dissertations Abstracts International 84-08B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.

Ann Arbor : ProQuest Dissertations & Theses, 2022

Language Note:

English

Summary:

In addition to high-affinity IgE receptor (FcεRI), a subtype of mast cells (MCs) found primarily in human skin, expresses a G protein-coupled receptor (GPCR) known as MRGPRX2 (mouse counterpart MrgprB2). Following agonist stimulation, GPCRs couple to G proteins to cause cellular activation but most receptors are also phosphorylated by GPCR Kinases (GRKs) to promote their desensitization. MCs express GRK2 but its role on the regulation of MRGPRX2/B2 and FcεRI function has not been studied in detail. For the present study, we generated mice with MC-specific deletion of GRK2 and utilized GRK2 inhibitors to determine if it differentially regulates MrgprB2 and FcεRI-mediated MC activation in vitro to modulate vascular permeability, rosacea, cutaneous anaphylaxis, and itch in vivo. Utilizing peritoneal MCs (PMCs) that express MrgprB2, we showed that the absence of GRK2 resulted in enhanced β-hexosaminidase release in response to compound 48/80 (C48/80) but significantly reduced tryptase release in response to the Cathelicidin LL37. Furthermore, absence of GRK2 resulted in increased cutaneous vascular permeability in response to C48/80 in vivo. By contrast, LL37-injection induced rosacea-like erythema, generation of matrix metalloproteinase 9 (MMP9), chemokine, CXCL2, and the recruitment of MCs and inflammatory cells in control mice but these responses were substantially reduced in GRK2-deleted mice. IgE-mediated anaphylaxis and itch were also significantly reduced in the absence of GRK2. Furthermore, in vitro studies with primary lung-derived MCs, which do not express MrgprB2, demonstrated that GRK2 deletion resulted in a significant reduction of IgE-mediated tyrosine phosphorylation of STAT5, calcium mobilization, and degranulation. GRK2 inhibitors (paroxetine and its analog CCG258747) inhibited FcεRI-induced calcium mobilization and degranulation, and their intravenous administration in mice resulted in substantial reduction of IgE-mediated anaphylaxis. However, both compounds induced calcium mobilization and degranulation via MRGPRX2 and MrgprB2 in vitro, and increased cutaneous vascular permeability in vivo. These findings suggest that while GRK2 regulation in MrgprB2 is most likely agonist dependent, it promotes IgE-mediated anaphylaxis and itch likely via tyrosine phosphorylation of STAT5.

Notes:

Source: Dissertations Abstracts International, Volume: 84-08, Section: B.

Advisors: Ali, Hydar; Committee members: Shin, Sunny; Haldar, Malay; Song, Wenchao; Kambayashi, Taku.

Department: Pharmacology.

Ph.D. University of Pennsylvania 2022.

Local Notes:

School code: 0175

ISBN:

9798374412093

Access Restriction:

Restricted for use by site license.

This item is not available from ProQuest Dissertations & Theses.