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 1

PBMCs from SLE patients exhibit low NLRP12 expression.

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PBMCs from SLE patients exhibit low NLRP12 expression. (A) NLRP12 expres...
(A) NLRP12 expression in SLE PBMCs relative to healthy controls was determined by quantitative reverse-transcriptase PCR (RT-qPCR). Relative NLRP12 expression was analyzed by the ΔΔCt = (ΔC_SLE–CtNorm(health)) and 2(–ΔΔCt) algorithm, and NLRP12 expression level in healthy controls was set as 1. Levels of (B) complement C3, (C) anti-dsDNA, and (D) anti-Sm Abs and corresponding NLRP12 expression were grouped and are shown. (E) Regression of NLRP12 expression and anti-Sm Abs. (F) Relative IFNA expression and corresponding NLRP12 expression were grouped and are shown. (G) Regression of NLRP12 and IFNA expression in SLE PBMCs. (H) Relative NLRP12 expression in PBMCs from SLE patients at visit follow-up. (I) NLRP12 expression in SLE monocytes relative to healthy monocytes. (J) Regression assay of NLRP12 and IFNA expression in SLE monocytes. (K and L) THP-1 cells were transfected with poly(I:C) and poly(dA:dT). NLRP12 and IFNA expression were measured. (M) NLRP12 expression of the IFN-α2–treated THP-1 cells. (N) Regression of NLRP12 expression of serum-treated THP-1 and levels of IFN-α in corresponding serum. (O) NLRP12 expression of serum-treated or 2-fold diluted serum-treated THP-1 cells. (P) THP-1 cells were treated with healthy (n = 10) or SLE (n = 24) sera. (Q) Sera from SLE patients (n = 24) with and without detectable IFN-α were grouped, and corresponding SLEDAI-2K was recorded. (B, C, and F) Two-tailed Student’s t test; (D, P, and Q) Mann-Whitney U test; (E, G, J, and N) Spearman’s correlation; (K–M) 1-way ANOVA test (multiple samples with mock control). Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.