Interferon (IFN)-inducible Absent in Melanoma 2 proteins in the negative regulation of the type I IFN response: Implications for lupus nephritis

Divaker Choubey, Ravichandran Panchanathan
Cytokine 2019 March 20
Systemic lupus erythematosus (SLE) is a complex autoimmune disease that exhibits a strong female bias (female-to-male ratio 9:1) in patients. Further, 40-60% SLE patients develop lupus nephritis (LN), which significantly increases the mortality rates. The failure of current therapies to adequately treat LN in patients reflects an incomplete understanding of the disease pathogenesis. Notably, a chronic increase in serum interferon-α (IFN-α) activity is a heritable risk factor to develop SLE. Accordingly, blood cells from most SLE patients with an active disease exhibit an increase in the expression of the type I IFN (IFN-α/β)-stimulated genes (ISGs, also referred to as "IFN-signature"), a type I IFN response. Further, LN patients during renal flares also exhibit an "IFN-signature" in renal biopsies. Therefore, an improved understanding of the regulation of type I IFNs expression is needed. Basal levels of the IFN-β through "priming" of IFN-α producing cells augment the expression of the IFN-α genes. Of interest, recent studies have indicated a role for the type I IFN-inducible Absent in Melanoma 2 proteins (the murine Aim2 and human AIM2) in the negative regulation of the type I IFN response through inflammasome-dependent and independent mechanisms. Further, an increase in the expression of Aim2 and AIM2 proteins in kidney and renal macrophages associated with the development of nephritis. Therefore, we discuss the role of Aim2/AIM2 proteins in the regulation of type I IFNs and LN. An improved understanding of the mechanisms by which the Absent in Melanoma 2 proteins suppress the type I IFN response and modulate nephritis is key to identify novel therapeutic targets to treat a group of LN patients.

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