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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish
Article numbere157272
JournalJournal of Clinical Investigation
Volume133
Issue number3
DOIs
StatePublished - 1 Feb 2023

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