NLRP3/Cryopyrin Is Necessary for Interleukin-1β (IL-1β) Release in Response to Hyaluronan, an Endogenous Trigger of Inflammation in Response to Injury

Abstract

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 whether 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 interleukin-1␤ (IL-1␤). Similarly, the addition of hyaluronan to macrophages derived from cryopyrin-deficient mice increased release of Cxcl2 but did not increase IL-1␤ release. To define the mechanism of hyaluronan-mediated activation of cryopyrin, elements of the hyaluronan recognition process were studied in detail. IL-1␤ release was inhibited in peritoneal macrophages derived from CD44-deficient mice, in an 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 lipopolysaccharide-primed macrophages. Therefore, the action of CD44 and subsequent hyaluronan catabolism trigger the intracellular cryopyrin 3 IL-1␤ pathway. These findings support the hypothesis that hyaluronan works through IL-1␤ and the cryopyrin system to signal sterile inflammation.Inflammation, as defined by changes in vascular permeability and leukocyte recruitment, is an essential step for the control of microbial invasion. Specific microbial products trigger this process through a diverse array of innate immune pattern recognition receptors. However, an inflammatory response independent of infection is also an important process for maintenance of biological homeostasis. For example, normal wound healing requires a controlled inflammatory response to enable the recruitment of monocytes and the release of growth factors required for repair. This response can occur in the absence of microbial stimuli. Furthermore, inflammation and the release of proinflammatory mediators is also associated with many diseases such as rheumatoid arthritis and Crohn disease (1). These diseases are not well understood in terms of their triggers but rather are described by the subsequent release of proinflammatory mediators. Identification of the triggers of sterile inflammation represents an important goal with immediate diagnostic and therapeutic significance.Recent work has begun to elucidate pathways of inflammation that occur in the absence of microbial stimuli. Stress signals such as heat-shock proteins, intracellular components of necrotic cells not normally seen by immune cells, and components of the extracellular matrix have all been implicated as endogenous triggers of injury (2-4). Among this group is the glycosaminoglycan hyaluronan (HA), 6 an important structural compo...

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