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 5

NLRP12 involved in innate immune signaling to negatively regulate cytokine production in response to nucleic acid stimulation.

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NLRP12 involved in innate immune signaling to negatively regulate cytoki...
(A) THP-1/sg-scramble and THP-1/sg-RUNX1 were transfected with poly(dA:dT), and gene expression was measured. (B) HEK293T cells were cotransfected with 100 ng of IFN-β luciferase reporter, indicated plasmids (STING, TBK1 or IRF-3), and empty vector (pCDNA3) or NLRP12-encoding plasmid (pCDNA3/HA-NLRP12, 300 ng/sample). Luciferase assays were performed at 24 hours. (C) Mouse BMDCs from WT and Nlrp12–/– mice were transfected with poly(dA:dT). Immunoblot was conducted and representative images and densitometry (relative to 0 hours) are shown. Bands were normalized with individual GAPDH. Ratio of phosphorylated protein to the total target protein was determined from 3 independent experiments. (D) WT and Nlrp12–/– BMDCs were transfected with poly(dA:dT). Cytokine production was measured at 24 hours. (E) Human CD14+ monocytes from healthy donors and SLE patients were transfected with poly(dA:dT). Representative blots and densitometry are shown (n = 6). (F) CD14+ monocytes from healthy donors (n = 8) and SLE patients (n = 10) were transfected with poly(dA:dT). Cytokine production was measured at 24 hours. (G) Human CD14+ monocytes were preincubated with Abs to IFNAR2 for 30 minutes followed by transfecting cells with poly(dA:dT). Gene expression was analyzed at 16 hours. (H) Heatmap showing 2 DEG comparisons: (i) healthy monocytes versus IFN-α2–treated healthy monocytes (IFN-α), and (ii) IFN-α2–treated healthy monocytes versus SLE monocytes in each category. Color bars indicate scores of log2-fold change for each comparison. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Student’s t test (A–E, G); Mann-Whitney U test (F).