Interestingly, one most recent study found that intracerebroventricular injection of recombinant human HMGB1 (rhHMGB1) in TLR4+/+ mice but not in TLR4-/- caused significantly more injury after cerebral ischemia-reperfusion than in the control group, suggesting that TLR4 contributes to HMGB1-mediated ischemic brain injury [20]. Here, TLR4 is linked to brain ischemia.