Clinical studies have shown that Aggregatibacter actinomycetemcomitans(A.actinomycetemcomitans)is associated with aggressive periodontitis and can potentially trigger or exacerbate rheumatoid arthritis(RA).However,the mechanism is poorly understood.Here,we show that systemic infection with A.actinomycetemcomitans triggers the progression of arthritis in mice anti-collagen antibody-induced arthritis(CAIA)model following IL-1β secretion and cell infiltration in paws in a manner that is dependent on caspase-11-mediated inflammasome activation in macrophages.The administration of polymyxin B(PMB),chloroquine,and anti-CD11b antibody suppressed inflammasome activation in macrophages and arthritis in mice,suggesting that the recognition of lipopolysaccharide(LPS)in the cytosol after bacterial degradation by lysosomes and invasion via CD11b are needed to trigger arthritis following inflammasome activation in macrophages.These data reveal that the inhibition of caspase-11-mediated inflammasome activation potentiates aggravation of RA induced by infection with A.actinomycetemcomitans.This work highlights how RA can be progressed by inflammasome activation as a result of periodontitis-associated bacterial infection and discusses the mechanism of inflammasome activation in response to infection with A.actinomycetemcomitans.

The immune-stromal cell interactions play a key role in health and diseases.In periodontitis,the most prevalent infectious disease in humans,immune cells accumulate in the oral mucosa and promote bone destruction by inducing receptor activator of nuclear factor-κB ligand(RANKL)expression in osteogenic cells such as osteoblasts and periodontal ligament cells.However,the detailed mechanism underlying immune-bone cell interactions in periodontitis is not fully understood.Here,we performed single-cell RNA-sequencing analysis on mouse periodontal lesions and showed that neutrophil-osteogenic cell crosstalk is involved in periodontitis-induced bone loss.The periodontal lesions displayed marked infiltration of neutrophils,and in silico analyses suggested that the neutrophils interacted with osteogenic cells through cytokine production.Among the cytokines expressed in the periodontal neutrophils,oncostatin M(OSM)potently induced RANKL expression in the primary osteoblasts,and deletion of the OSM receptor in osteogenic cells significantly ameliorated periodontitis-induced bone loss.Epigenomic data analyses identified the OSM-regulated RANKL enhancer region in osteogenic cells,and mice lacking this enhancer showed decreased periodontal bone loss while maintaining physiological bone metabolism.These findings shed light on the role of neutrophils in bone regulation during bacterial infection,highlighting the novel mechanism underlying osteoimmune crosstalk.

BACKGROUND: Maintenance of instrumental activities of daily living (IADL) and social role (SR) is crucial to keep independent life because the decline in SR and IADL was a significant predictor of dependence in basic ADL in later. The independent effect of physical and cultural leisure activities and their effect modification on the IADL remains unknown. METHODS: We prospectively observed 3241 elderly with intact IADL at baseline for 5 years. Higher level functional capacity such as IADL and SR was assessed using the Tokyo Metropolitan Institute of Gerontology Index of competence (TMIG index). RESULTS: The mean age of the participants was 72.3 years (standard deviation 5.1), and 46.9% were male, and 90.9% of them received a follow-up assessment. Of the participants, 10.4% developed an IADL decline. Engagement in leisure physical activity was associated with a significantly lower risk of IADL decline (adjusted risk ratio, 0.73; 95% confidence interval [CI], 0.60 to 0.89), and cultural leisure activity was also associated with lower risk of IADL decline (adjusted risk ratio, 0.77; 95% CI, 0.63 to 0.95) independent of potential confounders. We also found significant and positive interaction between physical and cultural leisure activities at risk for IADL decline (P = 0.024) and SR decline (P = 0.004). CONCLUSIONS We found an independent association of physical and cultural leisure activities with a lower risk for functional decline in IADL and SR with positive interaction. Combined engagement in physical and cultural activities may effectively prevent from IADL decline and SR decline.