Section of Endocrinology, Internal Medicine, School of Medicine, Yale University, New Haven, CT, United States.
Diabetes Research Group, Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Front Immunol. 2023 Feb 23;14:1147925. doi: 10.3389/fimmu.2023.1147925. eCollection 2023.
Gut microbiota have been linked to modulating susceptibility to Type 1 diabetes; however, there are many ways in which the microbiota interact with host cells, including through microbial ligand binding to intracellular inflammasomes (large multi-subunit proteins) to initiate immune responses. NLRP6, a microbe-recognizing inflammasome protein, is highly expressed by intestinal epithelial cells and can alter susceptibility to cancer, obesity and Crohn's disease; however, the role of NLRP6 in modulating susceptibility to autoimmune diabetes, was previously unknown.
We generated NLRP6-deficient Non-obese diabetic (NOD) mice to study the effect of NLRP6-deficiency on the immune cells and susceptibility to Type 1 diabetes development.
NLRP6-deficient mice exhibited an expansion of CD103 B cells and were protected from type 1 diabetes. Moreover, NLRP6-deficient CD103 B cells express regulatory markers, secreted higher concentrations of IL-10 and TGFb1 cytokines and suppressed diabetogenic T cell proliferation, compared to NLRP6-sufficient CD103 B cells. Microarray analysis of NLRP6-sufficient and -deficient CD103 B cells identified 79 significantly different genes including genes regulated by lipopolysaccharide (LPS), tretinoin, IL-10 and TGFb, which was confirmed in vitro following LPS stimulation. Furthermore, microbiota from NLRP6-deficient mice induced CD103 B cells in colonized NLRP6-sufficient germ-free mice; however, the long-term maintenance of the CD103 B cells required the absence of NLRP6 in the hosts, or continued exposure to microbiota from NLRP6-deficient mice.
Together, our data indicate that NLRP6 deficiency promotes expansion and maintenance of a novel TGF -dependent CD103 Breg population. Thus, targeting NLRP6 therapeutically may prove clinically useful.
肠道微生物群已被证明与调节 1 型糖尿病易感性有关；然而，微生物群与宿主细胞相互作用的方式有很多，包括通过微生物配体与细胞内炎症小体（大型多亚基蛋白）结合来启动免疫反应。NLRP6 是一种微生物识别的炎症小体蛋白，在肠上皮细胞中高度表达，可改变对癌症、肥胖和克罗恩病的易感性；然而，NLRP6 在调节自身免疫性糖尿病易感性方面的作用此前尚不清楚。
我们生成了 NLRP6 缺陷型非肥胖型糖尿病（NOD）小鼠，以研究 NLRP6 缺陷对免疫细胞和 1 型糖尿病发展易感性的影响。
NLRP6 缺陷型小鼠表现出 CD103 B 细胞的扩增，并对 1 型糖尿病具有保护作用。此外，与 NLRP6 充足的 CD103 B 细胞相比，NLRP6 缺陷型 CD103 B 细胞表达调节标记物，分泌更高浓度的 IL-10 和 TGFb1 细胞因子，并抑制致糖尿病 T 细胞增殖。NLRP6 充足和缺陷型 CD103 B 细胞的微阵列分析确定了 79 个显著差异基因，包括受脂多糖（LPS）、维甲酸、IL-10 和 TGFb 调节的基因，这在 LPS 刺激后的体外得到了证实。此外，NLRP6 缺陷型小鼠的微生物群可诱导定殖 NLRP6 充足的无菌小鼠中的 CD103 B 细胞；然而，CD103 B 细胞的长期维持需要宿主中 NLRP6 的缺失，或持续暴露于 NLRP6 缺陷型小鼠的微生物群。
总的来说，我们的数据表明，NLRP6 缺陷促进了新型 TGF-β依赖性 CD103 Breg 群体的扩张和维持。因此，靶向 NLRP6 进行治疗可能具有临床应用价值。
