Inflammation occurs following sterile injuries, as well as in response to microbial infection, and can lead to deleterious effects in various autoimmune diseases. Noting that the glycosaminoglycan hyaluronan (HA, a component of the extracellular matrix) activates Toll-like receptor 4 (TLR4), which is stimulated by the bacterial outer membrane component lipopolysaccharide (LPS) to mobilize elements of the inflammatory response, Taylor et al. investigated its role in mediating the inflammatory response to sterile injury. Mice lacking TLR4 produced less of the proinflammatory cytokine MIP-2 (macrophage inflammatory protein 2) than did wild-type mice in two models of sterile injury--subcutaneous injection of beads and localized freezing. Bead injection stimulated a localized increase in HA, and the ability of human wound fluid to stimulate MIP-2 secretion from the MH-S macrophage cell line--which was mimicked by HA but not by chondroitin sulfate or dermatan sulfate--was attenuated by treatment with chondroitinase ABC. Microarray analysis of MH-S cells treated with LPS or HA indicated that, although some genes showed increased expression in response to both treatments [for instance, those encoding interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)], the responses to these two treatments were distinct. HA and LPS also elicited distinct patterns of cytokine secretion. TLR4-dependent production of IL-8 in response to HA, like TLR4 signaling to LPS, depended on the soluble accessory protein MD-2. However, unlike LPS-dependent signaling, HA signaling through TLR4 did not involve CD14. Rather, HA signaling was enhanced by CD44 (a protein that serves as a receptor for HA and other ligands), which associated with TLR4 and MD-2. Thus, the authors propose that HA released from the extracellular matrix by injury acts through a TLR4 complex distinct from that mediating the inflammatory response to LPS to elicit a distinct inflammatory response.
K. R. Taylor, K. Yamasaki, K. A. Radek, A. Di Nardo, H. Goodarzi, D. Golenbock, B. Beutler, R. L. Gallo, Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on Toll-like receptor 4, CD44, and MD-2. J. Biol. Chem. 282, 18265-18275 (2007). [Abstract] [Full Text]