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<p><i>Porphyromonas gingivalis</i> (<i>Pg</i>), a gram-negative anaerobic bacterium, is a leading pathogen causing periodontitis. It secretes several virulence factors, including gingipains, lipopolysaccharides (LPS), and outer membrane vesicles (OMVs), which can trigger the release of inflammatory cytokines such as interleukin (IL)-1β, tumor necrosis factor alpha (TNFα), and IL-6 through inflammasome activation and Toll-like receptor (TLR) signaling. We demonstrated that <i>Pg</i> infection under hypoxic conditions enhances NLRP3 inflammasome activation in macrophages. Additionally, we observed that toll-interleukin-1 receptor domain-containing adaptor-inducing interferon-β (TRIF)-mediated hypoxia-inducible factor 1 alpha (HIF-1α) regulation exacerbates inflammasome activation under hypoxia. Notably, HIF-1α deficiency in myeloid cells reversed neurological symptoms and reduced IL-1β and IL-17 production in a mouse model of multiple sclerosis with <i>Pg</i> infection. Our findings indicated that hypoxia modulates inflammasome activation in response to periodontitis-related bacterial infections, contributing to the progression of autoimmune diseases.</p>

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Hypoxia drives progression of multiple sclerosis by enhancing the inflammasome activation in macrophages with Porphyromonas gingivalis infection

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月10日

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  • Tokuju Okano,
  • Hiroshi Ashida,
  • Masayuki Tsukasaki,
  • Tamako Iida,
  • Masahiro Yamamoto,
  • Hiroshi Takayanagi,
  • Takeharu Sakamoto,
  • Toshihiko Suzuki

摘要

Porphyromonas gingivalis (Pg), a gram-negative anaerobic bacterium, is a leading pathogen causing periodontitis. It secretes several virulence factors, including gingipains, lipopolysaccharides (LPS), and outer membrane vesicles (OMVs), which can trigger the release of inflammatory cytokines such as interleukin (IL)-1β, tumor necrosis factor alpha (TNFα), and IL-6 through inflammasome activation and Toll-like receptor (TLR) signaling. We demonstrated that Pg infection under hypoxic conditions enhances NLRP3 inflammasome activation in macrophages. Additionally, we observed that toll-interleukin-1 receptor domain-containing adaptor-inducing interferon-β (TRIF)-mediated hypoxia-inducible factor 1 alpha (HIF-1α) regulation exacerbates inflammasome activation under hypoxia. Notably, HIF-1α deficiency in myeloid cells reversed neurological symptoms and reduced IL-1β and IL-17 production in a mouse model of multiple sclerosis with Pg infection. Our findings indicated that hypoxia modulates inflammasome activation in response to periodontitis-related bacterial infections, contributing to the progression of autoimmune diseases.