1 NLRP 3 / cryopyrin is necessary for IL - 1 β release in response to hyaluronan , an endogenous trigger of inflammation in response to injury

Inflammation under sterile conditions is a key event in autoimmunity and following trauma. Hyaluronan, a glycosaminoglycan released from the extracellular matrix after injury, acts as an endogenous signal of trauma and can trigger chemokine release in injured tissue. Here we investigated if NLRP3/cryopyrin, a component of the inflammasome, participates in the inflammatory response to injury or the cytokine response to hyaluronan. Mice with a targeted deletion in cryopyrin showed a normal increase in Cxcl2 in response to sterile injuries but had decreased inflammation and release of IL-1β . Similarly, addition of hyaluronan to macrophages derived from cryopyrin-deficient mice increased release of Cxcl2 but did not increase IL-1β release. To define the mechanism of hyaluronan mediated activation of cryopyrin, elements of the hyaluronan recognition process were studied in detail. IL1β release was inhibited in peritoneal macrophages derived from CD44-deficient mice, in a MH-S macrophage cell line treated with antibodies to CD44, or by inhibitors of lysosome function. The requirement for CD44 binding and hyaluronan internalization could be bypassed by intracellular administration of hyaluronan oligosaccharides (10 – 18 mer) in LPS-primed macrophages. Therefore, the action of CD44 and subsequent hyaluronan catabolism trigger the intracellular cryopyrin ~ IL-1β pathway. These findings support the hypothesis that hyaluronan works through IL1β and the cryopyrin system to signal sterile inflammation.