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 8

NLRP12 deficiency enhances expansion of immune cells in Faslpr mice that exacerbates the progression of GN.

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NLRP12 deficiency enhances expansion of immune cells in Faslpr mice that...
(A) Weight of spleens and total number of splenocytes were recorded. (B) Number of splenic TCRβ+CD3+CD4–CD8– B220+ (DN) T cells and (C) expression levels of CD44 in DN T subset were analyzed by FACS. (D) Expression of Isg15 and Cxcl10 in splenocytes. (E) Amounts of serum IFN-α were measured by ELISA. (F) Numbers of splenic CD11B+and CD11C+ cells and (G) expression levels of MHC class II on CD11B+CD11C+ cells were analyzed by FACS. (H) Amounts of serum IL-6 were measured by ELISA. (I) Representative dot blots of the proportion of CD19+- and CD138+-expressing cells in splenocytes from mice. Compiled data (WT and Nlrp12–/–, n = 10; WT/lpr and Nlrp12–/–/lpr mice, n = 20) showed percentages of B cell (CD3–CD19+ CD138–) and plasma cell (CD3–CD19–CD138+) populations. (J) Levels of serum anti-dsDNA and anti-RNP Abs from WT/lpr and Nlrp12–/–/lpr mice were measured. (K) Representative IgG-stained WT/lpr mice and Nlrp12–/–/lpr glomeruli. (L) Representative CD43- and PAS-stained WT/lpr mice and Nlrp12–/–/lpr glomeruli at ninth month. Scale bars: 50 μm. (M) Measurement of urine ACR and (N) serum creatinine. (O) Percentages of glomerulus index distribution in WT/lpr and Nlrp12–/–/lpr mice. (A–E, F, and G) Shown are data from 28- to 30-week-old mice, n = 10–18; (E and H) 28- to 40-week-old mice, n = 20–28. (A, B, and F) One-way ANOVA; (C–E and G–N) 2-tailed Student’s t test. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.