8 research outputs found
Heparan sulfate as a regulator of inflammation and immunity
Heparan sulfate is found on the surface of most cell types, as well as in basement membranes and extracellular matrices. Its strong anionic properties and highly variable structure enable this glycosaminoglycan to provide binding sites for numerous protein ligands, including many soluble mediators of the immune system, and may promote or inhibit their activity. The formation of ligand binding sites on heparan sulfate (HS) occurs in a tissue- and context-specific fashion through the action of several families of enzymes, most of which have multiple isoforms with subtly different specificities. Changes in the expression levels of these biosynthetic enzymes occur in response to inflammatory stimuli, resulting in structurally different HS and acquisition or loss of binding sites for immune mediators. In this review, we discuss the multiple roles for HS in regulating immune responses, and the evidence for inflammation-associated changes to HS structure
C-terminal truncation of IFN- inhibits proinflammatory macrophage responses and is deficient in autoimmune disease
International audienceControlled macrophage differentiation and activation in the initiation and resolution of inflammation is crucial for averting progression to chronic inflammatory and autoimmune diseases. Here we show a negative feedback mechanism for proinflammatory IFN- activation of macrophages driven by macrophage-associated matrix metalloproteinase 12 (MMP12). Through C-terminal truncation of IFN- at 135Glu↓Leu136 the IFN- receptor-binding site was efficiently removed thereby reducing JAK-STAT1 signaling and IFN- activation of proinflammatory macrophages. In acute peritonitis this signature was absent in Mmp12 mice and recapitulated in Mmp12 mice treated with a MMP12-specific inhibitor. Similarly, loss-of-MMP12 increases IFN-–dependent proinflammatory markers and iNOS/MHC class II macrophage accumulation with worse lymphadenopathy, arthritic synovitis and lupus glomerulonephritis. In active human systemic lupus erythematosus, MMP12 levels were lower and IFN- higher compared to treated patients or healthy individuals. Hence, macrophage proteolytic truncation of IFN- attenuates classical activation of macrophages as a prelude for resolving inflammation