Hyaluronan Fragments Act as an Endogenous Danger Signal by Engaging TLR2

TLDR

Tissue injury degrades high‑molecular‑weight hyaluronan into low‑molecular‑weight fragments that act as danger signals, activating innate immunity. The study aims to show that low‑molecular‑weight hyaluronan activates innate immunity through TLR‑2. This activation occurs through a MyD88‑, IRAK‑, TRAF6‑, PKCζ‑, and NF‑κB‑dependent signaling cascade. High‑molecular‑weight hyaluronan suppresses TLR‑2 signaling, while low‑molecular‑weight hyaluronan enhances antigen‑specific T‑cell responses in vivo in wild‑type but not TLR‑2‑null mice.

Abstract

Abstract Upon tissue injury, high m.w. hyaluronan (HA), a ubiquitously distributed extracellular matrix component, is broken down into lower m.w. (LMW) fragments, which in turn activate an innate immune response. In doing so, LMW HA acts as an endogenous danger signal alerting the immune system of a breach in tissue integrity. In this report, we demonstrate that LMW HA activates the innate immune response via TLR-2 in a MyD88-, IL-1R-associated kinase-, TNFR-associated factor-6-, protein kinase Cζ-, and NF-κB-dependent pathway. Furthermore, we show that intact high m.w. HA can inhibit TLR-2 signaling. Finally, we demonstrate that LMW HA can act as an adjuvant promoting Ag-specific T cell responses in vivo in wild-type but not TLR-2null mice.