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.
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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 7

NLRP12-deficient mice presented more severe disease course in the pristane-induced lupus-like model.

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NLRP12-deficient mice presented more severe disease course in the prista...
(A) Levels of serum anti-dsDNA Abs and (B) anti-RNP Abs in WT and Nlrp12–/– mice were measured. (C) Immunofluorescence staining of IgG from kidney sections at fifth, seventh, and ninth months in WT and Nlrp12–/– mice. (D) FACS analysis of population of myeloid immune cells in kidney including inflammatory monocytes, Mac2+ macrophages, granulocytes, and CD11C+ cells. (E) Representative CD430- and (F) PAS-stained WT and Nlrp12–/– glomeruli. (G) Calculation of the average of mesangial area in glomerulus using the MetaMorph Imaging System (Molecular Devices). (H) Measurement of mouse urine ACR. (I) Measurement of mouse serum creatinine. (J) Representative IgG-, CD43-, and PAS-stained Nlrp12–/–Ifnar1–/– and Nlrp12–/– glomeruli at the ninth month. (K) Representative IgG- and PAS-stained glomeruli from WT and Nlrp12–/– mice treated with IMQ for 5 weeks. Two-tailed Student’s t test. Data are represented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Scale bars: 50 μm.