Downregulated NLRP3 and NLRP1 inflammasomes signaling pathways in the development and progression of type 1 diabetes mellitus.

BACKGROUND: NLRP3 and NLRP1 inflammasomes signaling pathways may play an important role in the development and progression of type 1 diabetes mellitus (T1DM). However, relative research is rare.

METHODS: The blood mononuclear cells (PBMCs) and granulocytes (GCs) were collected from T1DM patients. The mRNA and protein expression levels were detected by qRT-PCR and Western blotting, respectively. The NLRP3/NLRP1was knocked down by transfected with siRNA, or ovexpressed by infected with lentiviral vectors in PBMCs and GCs from non obese diabetic (NOD) mice, respectively. The occurrence of diabetes was evaluated and the intraperitoneal glucose tolerance was tested in NOD mice with IL-1 receptor-associated kinase-M deficiency (IRAK-M-/- ). The pancreas and lymphonodus of IRAK-M-/- NOD mice were also collected for detection of NLRP3/NLRP1 expression.

RESULTS: NLRP3, NLRP1, Caspase-1and IL-1β were significantly downregulated in the PBMCs and GCs of patients with T1DM, and NLRP3 and NLRP1 were markedly downregulated in T1DM patients with DKA compared to that with ND and CC. Further study indicated that IL-1β mRNA expression level was positively correlated with the expression levels of NLRP3, NLRP1 and Caspase-1. Besides, NLRP3/NLRP1 knockdown decreased the expression levels of Caspase-1 and IL-1β; whereas NLRP3/NLRP1 overexpression increased the expression levels of Caspase-1 and IL-1β in vitro. IRAK-M-/- NOD mice had early onset and rapid progression of T1DM, and weak glucose tolerance, which was regarded as an early T1D mouse model. The mRNA expression levels of NLRP3, NLRP1, Caspase-1and IL-1β in the pancreas and lymphonodus of IRAK-M-/- NOD mice were significantly higher compared to that of IRAK-M+/+ NOD mice.

CONCLUSION: NLRP3 and NLRP1 inflammasomes signaling pathways were associated with the development and progression of T1DM, which response as protective factors in the early stage of T1DM.