Abstract
Background Signaling driven by nucleic acid sensors participates in interferonopathy-mediated autoimmune diseases. NLRP12, a pyrin-containing NLR protein, is a negative regulator of innate immune activation and type I interferon (IFN-I) production.
Methods SLE patients enrolled in this study will be analyzed the NLRP12 and IFNA expression in their Peripheral blood mononuclear cells (PBMCs), and their corresponding serological markers were recorded to determine the correlation between level of NLRP12 expression and serological markers. Regulation of NLRP12 expression was analyzed with the luciferase reporter assay, and the specific transcription factor on the NLRP12 promoter was determined with the chromatin immunoprecipitation assay (ChIP) in SLE PBMCs. The spontaneous activation of SLE PBMCs and the hyperresponsiveness of SLE PBMCs to nucleic acid stimulation toward cytokine production was analyzed. Nlrp12 deficient mouse was applied to confirm the role of NLRP12 in the pathogenesis of lupus progression.
Results PBMCs derived from systemic lupus erythematosus (SLE) patients expressed lower levels of NLRP12, with an inverse correlation with IFNA expression and high disease activity. NLRP12 expression was transcriptionally suppressed by runt-related transcription factor 1–dependent (RUNX1-dependent) epigenetic regulation under IFN-I treatment, which enhanced a negative feedback loop between low NLRP12 expression and IFN-I production. Reduced NLRP12 protein levels in SLE monocytes were linked to spontaneous activation of innate immune signaling and hyperresponsiveness to nucleic acid stimulations. Pristane-treated Nlrp12–/– mice exhibited augmented inflammation and immune responses; and substantial lymphoid hypertrophy was characterized in NLRP12-deficient lupus-prone mice. The NLRP12 deficiency mediated- increase of autoantibody production, intensive glomerular IgG deposition, monocyte recruitment, and the deterioration of kidney function were bound to IFN-I signature-dependent manner in the mouse models.
Conclusions These findings highlight a relationship between low NLRP12 expression and SLE progression with implications as a treatment target. We also suggest the level of NLRP12 expression on homeostasis and immune resilience.
