The study shows that the antimicrobial peptide LL‑37 can trigger mast cells in the gums to release inflammatory chemicals, and that a specific form of bacterial lipopolysaccharide from the gum‑pathogen P. gingivalis can block this effect. This suggests LL‑37 isn’t just an antimicrobial; it can also promote inflammation in the mouth, which may worsen gum disease if mast cells are over‑active.

<i>Porphyromonas gingivalis</i> is a keystone pathogen that contributes to periodontal pathogenesis by disrupting host-microbe homeostasis and promoting dysbiosis. The virulence of <i>P. gingivalis</i> likely reflects an alteration in the lipid A composition of its lipopolysaccharide (LPS) from the penta-acylated (<i>Pg</i>LPS₁₆₉₀) to the tetra-acylated (<i>Pg</i>LPS_1435/1449) form. Mast cells play an important role in periodontitis, but the mechanisms of their activation and regulation remain unknown. The expression of epithelium- and neutrophil-derived host defense peptides (HDPs) (LL-37 and human &#x3b2;-defensin-3), which activate mast cells via Mas-related G protein-coupled receptor X2 (MRGPRX2), is increased in periodontitis. We found that MRGPRX2-expressing mast cells are present in normal gingiva and that their numbers are elevated in patients with chronic periodontitis. Furthermore, HDPs stimulated degranulation in a human mast cell line (LAD2) and in RBL-2H3 cells stably expressing MRGPRX2 (RBL-MRGPRX2). <i>Pg</i>LPS₁₆₉₀ caused substantial inhibition of HDP-induced mast cell degranulation, but <i>Pg</i>LPS_1435/1449 had no effect. A fluorescently labeled HDP (FAM-LL-37) bound to RBL-MRGPRX2 cells, and <i>Pg</i>LPS₁₆₉₀ inhibited this binding, but <i>Pg</i>LPS_1435/1449 had no effect. These findings suggest that low-level inflammation induced by HDP/MRGPRX2-mediated mast cell degranulation contributes to gingival homeostasis but that sustained inflammation due to elevated levels of both HDPs and MRGPRX2-expressing mast cells promotes periodontal disease. Furthermore, differential regulation of HDP-induced mast cell degranulation by <i>Pg</i>LPS₁₆₉₀ and <i>Pg</i>LPS_1435/1449 may contribute to the modulation of disease progression.