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.

Sarcoid‐like reaction in a child following prolonged therapeutic exposure to dabrafenib and trametinib for BRAF V600E mutated hypothalamic/chiasmatic glioma

“…14,15 Not only can NLRP12 mutations lead to varied systemic autoimmune manifestations, reduced NLRP12 expression has been linked to more severe phenotypes of other autoimmune disorders like lupus in preclinical models. 16 Though no reports of S/SLR have been reported, it is intriguing to postulate whether the novel variant in NLRP12 could have contributed to the risk of a drug-induced S/SLR in our patient.…”

Allogeneic cord blood regulatory T cells decrease dsDNA antibody and improve albuminuria in systemic lupus erythematosus

“…At a fundamental level, the co-culture of CD4 + CD25 + CD127 low UCB-Tregs with SLE-PBMC shifts the dominance of CD8 + Teffs and CD19 + lupus B cells towards the CD4 + CD25 + CD127 low Treg phenotype and CD4 + CD8 + dual expressing T cells, which have been shown to have a suppressive effect on the production of autoantibodies including anti-dsDNA Ab in SLE ( 30 ). CD4 + CD25 + CD127 low UCB-Tregs decrease the percentage of pathogenic monocytes, which have been shown to be associated with deterioration of kidney function in lupus patients ( 31 ). In fact, our CD4 + CD25 + CD127 low UCB-Tregs were able to continue their IL-10 secretion, a well-described suppressive cytokine, to inhibit the proliferation of pathogenic SLE-PBMCs in vitro .…”

The Interplay between Immune and Metabolic Pathways in Kidney Disease

“…NF-κB is a transcription factor that regulates the expression of genes involved in inflammation and immune cell activation, and its dysregulation has been shown to contribute to the development of lupus nephritis [ 144 , 145 ]. The type I IFN pathway is another important pathway involved in the activation of immune cells in lupus nephritis, as the overexpression of type I IFN-inducible genes has been observed in lupus nephritis patients [ 146 , 147 , 148 ].…”