Figure 1.

Coordinate regulation of fibroinflammation by TGF-β and hyaluronan. TGF-β induces the expression of HAS resulting in the increased synthesis and release of hyaluronan. Binding of hyaluronan to CD44 results in the formation of a lipid raft-localized CD44/EGFR complex leading to the activation of ERK and CAM kinases, which regulate expression of α-SMA and myofibroblast differentiation. Hyaluronan occupancy of CD44 also promotes the TLR4-dependent induction of NF-κB-dependent proinflammatory cytokines, including IL-6, IL-8, and TNFα. α-SMA, α-smooth muscle cell actin; EGFR, epidermal growth factor receptor; HAS, hyaluronic acid synthase; TGF-β, transforming growth factor beta.