NLRP12 is an innate immune checkpoint for repressing IFN signatures and attenuating lupus nephritis progression
Yen-Po Tsao, Fang-Yu Tseng, Chih-Wei Chao, Ming-Han Chen, Yi-Chen Yeh, Babamale Olarewaju Abdulkareem, Se-Yi Chen, Wen-Ting Chuang, Pei-Ching Chang, I-Chun Chen, Pin-Hsuan Wang, Chien-Sheng Wu, Chang-Youh Tsai, Szu-Ting Chen
Yen-Po Tsao, Fang-Yu Tseng, Chih-Wei Chao, Ming-Han Chen, Yi-Chen Yeh, Babamale Olarewaju Abdulkareem, Se-Yi Chen, Wen-Ting Chuang, Pei-Ching Chang, I-Chun Chen, Pin-Hsuan Wang, Chien-Sheng Wu, Chang-Youh Tsai, Szu-Ting Chen
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Research Article Autoimmunity Inflammation

NLRP12 is an innate immune checkpoint for repressing IFN signatures and attenuating lupus nephritis progression

Abstract

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. Peripheral blood mononuclear cells (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 was 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. NLRP12 deficiency mediated the increase of autoantibody production, intensive glomerular IgG deposition, monocyte recruitment, and the deterioration of kidney function. These were bound in an IFN-I signature–dependent manner in the mouse models. Collectively, we reveal a remarkable link between low NLRP12 expression and lupus progression, which suggests the impact of NLRP12 on homeostasis and immune resilience.

Authors

Yen-Po Tsao, Fang-Yu Tseng, Chih-Wei Chao, Ming-Han Chen, Yi-Chen Yeh, Babamale Olarewaju Abdulkareem, Se-Yi Chen, Wen-Ting Chuang, Pei-Ching Chang, I-Chun Chen, Pin-Hsuan Wang, Chien-Sheng Wu, Chang-Youh Tsai, Szu-Ting Chen

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Figure 4

HDAC is involved in IFN-I–mediated transcriptional suppression of NLRP12 expression.

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HDAC is involved in IFN-I–mediated transcriptional suppression of NLRP12...
(A and B) THP-1 cells were preincubated with inhibitors for 30 minutes followed by treating cells with IFN-α2 for 6 hours. NLRP12 expression was measured. (B) Restoration of NLRP12 expression was calculated by setting NLRP12 expression in IFN-α2–treated cells (DMSO) as 1. Relative NLRP12 expression in the presence of inhibitors to DMSO group was measured. (C) THP-1/sg-scramble and THP-1/sg-RUNX1 were preincubated with TSA and SAHA and then treated with IFN-α2. NLRP12 expression was measured. (D and E) THP-1/sg-scramble and THP-1/sg-RUNX1 treated with IFN-α2 were collected for ChIP analysis, in which the DNA-protein complex was pulled down by using control IgG and Abs to HDAC1 and acetyl-histone 3. Region of NLRP12 promoter and 3′ UTR was amplified as in previous description. (F) PBMCs (n = 5) from healthy donors and SLE patients were collected for ChIP analysis using a control IgG and an Ab to HDAC1. Region of NLRP12 promoter was amplified. (G) PBMCs from SLE patients (n = 10) were treated with DMSO or TSA for 4 hours.NLRP12 expression relative to healthy PBMCs (n = 10) was measured. (H) CD14+ monocytes (n = 3) were treated with TSA for the entire period or for 4 hours, and TSA was removed, cells were transfected with poly(dA:dT), and IFNA expression was measured at 16 hours. (A) Two-tailed Student’s t test; (B–E, G, and H) 1-way ANOVA (multiple samples to the DMSO, or mock, or healthy control); (F) Mann-Whitney U test. Data are represented as mean ± SEM (n ≥ 5). *P < 0.05; **P < 0.01; ***P < 0.001.