Metabolic syndrome, systemic autoimmunity and type I interferons:a ménage à trois

posted Jan 26, 2017, 1:08 AM by sourav ghosh   [ updated Jan 26, 2017, 3:06 AM ]
Dipyaman Ganguly
Senior Scientist & Ramanujan Fellow, IICB-Translational, Research Unit of Excellence, CSIR-Indian Institute of Chemical Biology, Kolkata India

Plasmacytoid dendritic cells (pDC) are major producers of type I interferons (IFN-I) in response to recognition of pathogen-derived nucleic acid molecules by endosomal toll-like receptors (TLRs). Involvement of pDC-derived IFN-I in a number of autoimmune diseases as well is established. Recognition of self-nucleic acids leads to induction of IFN-I from pDCs and drives innate initiation of inflammation in Systemic Lupus Erythematosus (SLE), Psoriasis and a number of other autoimmune contexts. Thus induction of pDC-derived IFN-I is a shared initiator event in discreet clinical contexts, leading to a model where these clinical contexts are grouped together as a syndrome of inadvertent pDC activation. We propose the name ‘Plasmacytoidopathy’.
Interestingly, we also identified role of pDC-derived IFN-I in obesity associated metaflammation and insulin resistance. We found chemerin, an adipose-derived chemokine, recruits pDCs in obese adipose tissue and initiates the metaflammation cascade. TLR9 activation in recruited PDC induces IFN-I, which drive in situ macrophage polarization and adipose tissue insulin resistance. Of note, systemic autoimmune contexts are often associated with insulin resistance. We actually could link systemic IFN-I response with susceptibility to insulin resistance in an autoimmune context. In rodent models of the disease TLR9 deficiency has also recently been shown to ameliorate insulin resistance, thus validating our model. Moreover, a distinct autoantibody response can be detected in obese individuals, like IFN-I-driven autoimmunities.
We think that a syndromic description (‘Plasmacytoidopathy’) of these different clinical contexts, from systemic autoimmune diseases to metabolic derangements, will enable identification of important biomarkers as well as novel therapeutic targets.