Suppressing suppressors to improve lupus?

Lupus patients have more inflammation and more interferon type I (alphas, beta).  SLE monocytes have less NLRP12, which is part of certain inflammasome.and contributes to the activation of pro-inflammatory caspases.  TLR7 is important in lupus.  The authors note that NLRP12 was ‘recently identified’ (citing a 2012 paper) as a negative regulator of TLR and NFkB activation. 

They found (Fig 1) NLRP12 expression is lower in lupus patients than in healthy controls and it is inversely correlated with type I interferon (IFN-a2) expression; (Fig 2) RUNX1 binding sequences in the NRLP12 promoter reduced expression of a reporter gene and CRISPR knockout of RUNX1 increased NLRP12 expression induced by IFN or virus; (Fig 3) there is more RUNX1 and less NLRP12 in monocytes from lupus patients (panels I, shown) and more RUNX1 binding to NLRP12 promoters in PBMC of lupus patients (panel J). (Fig 4) IFN-induced suppression of NLRP12 is mediated by histone acetylation; (Fig 5) RUNX1 reduces NLRP12, which increases IFN, which is (also) observed in SLE; (Fig 6) NLRP12-KO mice are more pro-inflammatory and (Fig 7 & 8) develop worse disease in mouse models of lupus (pristane injection or Fas-lpr).

Figure 3, panels I&J. Panel I immunoblot of proteins in lysates of CD14+ monocytes, quantified on right. Panel J ChIP (chromosome immunoprecipitation) of PBMC.

They do a very good job connecting pointillist dots.

Tsao YP, Tseng FY, Chao CW, Chen MH, Yeh YC, Abdulkareem BO, Chen SY, Chuang WT, Chang PC, Chen IC, Wang PH, Wu CS, Tsai CY, Chen ST. NLRP12 is an innate immune checkpoint for repressing IFN signatures and attenuating lupus nephritis progression. J Clin Invest. 2023 Feb 1;133(3):e157272. doi: 10.1172/JCI157272. PMID: 36719379.