Tissue-specific mechanisms regulate neutrophil immunity at the oral barrier, which plays a key role in periodontitis. Although it has been proposed that fibroblasts emit a powerful neutrophil chemotactic signal, how this chemotactic signal is driven has not been clear. The objective of this study was to investigate the site-specific regulatory mechanisms by which fibroblasts drive powerful neutrophil chemotactic signals within the oral barrier, with particular emphasis on the role of the IL-36 family. The present study found that IL-36γ, agonist of IL-36R, could promote neutrophil chemotaxis via fibroblast. Single-cell RNA sequencing data disclosed that IL36G is primarily expressed in human and mouse gingival epithelial cells and mouse neutrophils. Notably, there was a substantial increase in IL-36γ levels during periodontitis. In vitro experiments demonstrated that IL-36γ specifically activates gingival fibroblasts, leading to chemotaxis of neutrophils. In vivo experiments revealed that IL-36Ra inhibited the infiltration of neutrophils and bone resorption, while IL-36γ promoted their progression in the ligature-induced periodontitis mouse model. In summary, these data elucidate the function of the site-enriched IL-36γ in regulating neutrophil immunity and bone resorption at the oral barrier. These findings provide new insights into the tissue-specific pathophysiology of periodontitis and offer a promising avenue for prevention and treatment through targeted intervention of the IL-36 family.

中文翻译：

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IL-36 调节中性粒细胞趋化性和口腔屏障处的骨丢失

组织特异性机制调节口腔屏障的中性粒细胞免疫，这在牙周炎中起着关键作用。尽管有人提出成纤维细胞发出强大的中性粒细胞趋化信号，但这种趋化信号是如何驱动的尚不清楚。本研究的目的是调查成纤维细胞在口腔屏障内驱动强大的中性粒细胞趋化信号的位点特异性调节机制，特别强调 IL-36 家族的作用。本研究发现IL-36γ（IL-36R的激动剂）可以通过成纤维细胞促进中性粒细胞趋化性。单细胞RNA测序数据显示IL36G主要在人和小鼠牙龈上皮细胞和小鼠中性粒细胞中表达。值得注意的是，牙周炎期间 IL-36γ 水平大幅增加。体外实验表明，IL-36γ特异性激活牙龈成纤维细胞，导致中性粒细胞趋化。体内实验表明，在结扎诱导的牙周炎小鼠模型中，IL-36Ra 抑制中性粒细胞浸润和骨吸收，而 IL-36γ 则促进其进展。总之，这些数据阐明了位点富集的 IL-36γ 在调节中性粒细胞免疫和口腔屏障骨吸收中的功能。这些发现为牙周炎的组织特异性病理生理学提供了新的见解，并为通过 IL-36 家族的靶向干预来预防和治疗提供了一条有前途的途径。