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 6

NLRP12-deficient mice display greater immune response and higher IFN-I production in response to pristane injection.

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NLRP12-deficient mice display greater immune response and higher IFN-I p...
Mice receiving pristane injection were sacrificed at indicated time points. (A) Numbers of infiltrated cells in the peritoneal cavity were recorded. (B) Amount of TNF in peritoneal lavage fluid was measured by cytometric bead array (CBA) analysis. (C) The numbers and percentages of recruited inflammatory monocytes were measured by FACS. (D) The gene expression of IFN signatures in PECs was measured; data were displayed with ΔCt, which stands for absolute gene expression level. (E) Representative immunoblots of the PECs at 1 month after injection and quantitative densitometry are shown. (F) IFN-α expression in peritoneal Ly6ChiCCR2hiCD11B+CD11C–F4/80+ inflammatory monocytes and CD11B+CD11C+F4/80+Ly6C–Ly6G– DCs was measured by FACS. Histogram from a representative sample at 0.5 months after injection (left). Data compilations (n = 6~9, right) were expressed as the MFI relative to the corresponding isotype control. (G) IFN-α amounts in peritoneal lavage fluid were measured by ELISA. (H) Relative MHC class II (MHC II) expression of splenic CD11C+ DCs and (I) relative CD44 expression of splenic CD4+ T cells were measured by FACS. (J) Representative dot blots of the proportion of CD19+- and CD138+-expressing cells in splenocytes from mice at 3 months after injection (left). Data (n = 8 each, right) show percentages of B cell (CD3–CD19+) and plasma cell (CD3–CD19–CD138+) populations. Percentages of plasma cells were compared between WT and Nlrp12–/– mice and analyzed with 2-tailed Student’s t test. (F–I). Two-tailed Student’s t test. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.