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NLRP12 is an innate immune checkpoint for repressing IFN signatures and attenuating lupus nephritis progression
Yen-Po Tsao, … , Chang-Youh Tsai, Szu-Ting Chen
Yen-Po Tsao, … , Chang-Youh Tsai, Szu-Ting Chen
Published February 1, 2023
Citation Information: J Clin Invest. 2023;133(3):e157272. https://doi.org/10.1172/JCI157272.
View: Text | PDF | Corrigendum
Research Article Autoimmunity Inflammation

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

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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 3

Increased binding of RUNX1 to the NLRP12 promoter region.

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Increased binding of RUNX1 to the NLRP12 promoter region.
(A and B) THP-...
(A and B) THP-1 cells treated with IFN-α2 or infected with VSV. RUNX1 expression was determined at indicated time points. (C) Human CD14+ monocytes treated with IFN-α2 or infected with VSV. Levels of nuclear RUNX1 protein were analyzed with immunoblot. Histone 3 was used as a loading control. (D) Schematic representation of NLRP12 gene from (+1). Vertical lines represent putative RUNX1-binding motifs. The locations of the EMSA probe and PCR products that are covered with the 2 RUNX1-binding sites or 3′ UTR of the NLRP12 promoter are shown. (E and F) Nuclear extracts obtained from CD14+ monocytes were treated with IFN-α2 or VSV. EMSA was conducted by using a biotin-labeled probe, and excess unlabeled probe was used to compete for this binding to validate the binding specificity. (G and H) CD14+ monocytes treated with IFN-α2 or VSV for 2 and 4 hours followed by a ChIP assay. (I) Lysates from CD14+ monocytes of healthy donors (n = 14) and SLE patients (n = 18) were subjected to immunoblot analysis. Representative image and quantitative densitometry are shown. (J) PBMCs from healthy donors and SLE patients (n = 11) were collected for ChIP analysis. (A–H) One-way ANOVA (multiple samples to the mock control); (I) 2-tailed Student’s t test; (J) Mann-Whitney U test. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.

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