The authors describe the immunoregulatory contributions of intact versus fragmented hyaluronan, a prominent component of the extracellular matrix.

The composition of the ECM provides contextual cues to leukocytes in inflamed and healing tissues. One example of this is HA, where LMW–HA, generated during active inflammation, is a TLR ligand and an endogenous “danger signal,” and HMW–HA, predominant in healing or intact tissues, functions in an inverse manner. Our data suggest that HMW–HA actively promotes immune tolerance by augmenting CD4+CD25+ T_Reg function, and LMW–HA does not. Using a human iT_Reg model, we demonstrate that HMW–HA but not LMW–HA provides a costimulatory signal through cross–linking CD44 which promotes Foxp3 expression, a critical signaling molecule associated with T_Reg. This effect, in part, may be mediated by a role for intact HMW–HA in IL–2 production, as T_Reg are highly IL–2–dependent for their survival and function. We propose that HMW–HA contributes to the maintenance of immune homeostasis in uninjured tissue and effectively communicates an “all–clear” signal to down–regulate the adaptive immune system through T_Reg after tissue matrix integrity has been restored.