Role of a novel G protein-coupled mast cell receptor-mediated pathways in periodontal disease

Summary:
Periodontitis is a chronic inflammatory disease in which a highly orchestrated host-microbial interaction leads
to the destruction of the tooth-supporting structures including periodontal tissue attachment and alveolar bone.
Mast cells are found in the gingiva; their numbers are increased in chronic periodontitis and the degree of their
activation correlates well with disease severity. Not surprisingly, it has recently been shown that mast cells
contribute to Porphyromonas gingivalis-induced periodontitis in mice, but the mechanisms involved in their
activation and regulation remain unknown. Mas-related G protein-coupled receptor X2 (MRGPRX2, mouse
counterpart MrgprB2) is a newly described cell surface receptor that is expressed in a subtype of mast cells
found predominantly in the skin and the gingiva. We recently demonstrated that MRGPRX2-expressing mast
cells are present in normal gingiva and that their numbers are increased in patients with chronic periodontitis.
In addition, our unpublished preliminary data demonstrated that compared to wild-type mice, MrgprB2-/- mice
are protected from mast cell recruitment, gingival inflammation, and bone loss in a ligature-induced model of
periodontitis. Based on these findings, we hypothesize that recruitment and activation of mast cells
through MRGPRX2/B2 contribute to periodontitis. In aim 1, we will develop two models of humanized mice.
The first involves retroviral transduction of MRGPRX2 into MrgprB2-/- mouse bone marrow stem cells, their
differentiation into bone marrow-derived MCs (BMMCs) ex vivo and their engraftment into mast cell-deficient
Wsh/Wsh mice. The second involves CRISPR/Cas9-mediated replacement of MrgprB2 with MRGPRX2. These
humanized mice will be used to study Porphyromonas gingivalis and ligature-induced periodontitis. In aim 2,
we will modulate periodontitis by targeting MRGPRX2/MrgprB2-mediated cofilin and NF-κB signaling in mast
cells. Successful completion of this study will lead to the development of new preclinical models to modulate
periodontitis through specific small molecule receptor antagonists and by targeting signaling in mast cells.

Grant Number: 1R21DE033537-01A1
NIH Institute/Center: NIH
Principal Investigator: Hydar Ali