Toll-like receptor 2/4 heterodimer mediates inflammatory injury in intracerebral hemorrhage

Objective Inflammatory injury plays a critical role in intracerebral hemorrhage (ICH)‐induced secondary brain injury. However, the upstream events that initiate inflammatory responses following ICH remain elusive. Our previous studies suggested that Toll‐like receptor 4 (TLR4) may be the upstream signal that triggers inflammatory injury in ICH. In addition, recent clinical findings indicated that both TLR2 and TLR4 may participate in ICH‐induced brain injury. However, it is unclear how TLR2 functions in ICH‐induced inflammatory injury and how TLR2 interacts with TLR4. Methods The role of TLR2 and TLR2/TLR4 heterodimerization in ICH‐induced inflammatory injury was investigated in both in vivo and in vitro models of ICH. Results TLR2 mediated ICH‐induced inflammatory injury, which forms a heterodimer with TLR4 in both in vivo and in vitro models of ICH. Hemoglobin (Hb), but not other blood components, triggered inflammatory injury in ICH via assembly of TLR2/TLR4 heterodimers. MyD88 (myeloid differentiation primary response gene 88), but not TRIF (Toll/IR‐1 domain–containing adaptor protein inducing interferon‐beta), was required for ICH‐induced TLR2/TLR4 heterodimerization. Mutation of MyD88 Arg196 abolished the TLR2/TLR4 heterodimerization. Interpretation Our results suggest that a novel TLR2/TLR4 heterodimer induced by Hb initiates inflammatory injury in ICH. Interfering with the assembly of the TLR2/TLR4 heterodimer may be a novel target for developing effective treatment of ICH. Ann Neurol 2014;75:876–889