# Inhibition of BTK and SYK attenuates Porphyromonas gingivalis -induced activation of the pyroptosis pathway and inflammation in host cells

## TL;DR

This study shows that BTK and SYK inhibitors reduce inflammation and cell death caused by a bacteria linked to gum disease, suggesting new treatment options.

## Contribution

The study reveals that BTK and SYK inhibitors can broadly suppress pyroptosis and inflammation in immune and oral tissue cells infected with Porphyromonas gingivalis.

## Key findings

- Ibrutinib and R406 inhibit NLRP3 pyroptosis and IL-1β secretion in macrophages infected with Porphyromonas gingivalis.
- Both inhibitors reduce pro-inflammatory cytokines like IL-6, IL-8, and TNFα in macrophages and fibroblasts.
- Ibrutinib uniquely suppresses M1-like polarization and ROS in macrophages, while both drugs broadly reduce inflammation in fibroblasts.

## Abstract

Periodontitisis a chronic inflammatory disease of the oral cavity, primarily driven by periodontopathogens such as Porphyromonas gingivalis (Pg)."

We investigated the therapeutic potential of BTK and SYK inhibitors on the pathological processes induced by two Pg strains, ATCC 33277 and W83, in human monocyte-derived macrophages (hMDMs) and human gingival fibroblasts (hGFs).

hMDM and hGF were infected with Pg strains and assessed for viability, inflammatory activation, and phenotype, with or without the BTK inhibitor ibrutinib or SYK inhibitor R406, under acute and chronic infection conditions.

Ibrutinib and R406 suppressed Pg infection-induced activation of the NLRP3-dependent pyroptosis pathway and IL-1β secretion in hMDMs. Both compounds also significantly reduced IL-6, IL-8, and TNFα release by hMDM in both infection models, regardless of differences between ATCC 33277 and W83 Pg strains. Ibrutinib and R406 potently suppressed inflammatory activation of hGFs, including IL-6 and IL-8 production, and NF-κB p65 phosphorylation triggered by the more immunostimulatory ATCC 33277 strain.

The pharmacological inhibition of BTK or SYK mitigates the pyroptotic pathway in hMDMs and exerts a broad anti-inflammatory effect in both hMDMs and hGFs. These results highlight the anti-inflammatory potential of BTK and SYK inhibitors for the treatment of periodontal disease.

Ibrutinib and R406 suppress Pg-induced pyroptosis signaling and pro-inflammatory cytokine release in hMDMs across different Pg strains and infection models.

Ibrutinib uniquely inhibits M1-like polarization and ROS production in hMDMs, while both inhibitors broadly reduce inflammatory activation in hGFs, indicating distinct and complementary immunomodulatory effects.

These findings highlight BTK and SYK inhibition as promising therapeutic strategies to mitigate inflammation and tissue damage in periodontitis (PD), particularly in the context of chronic inflammation, which may be associated with cell senescence.