Fig. 4

ROS-mediated HMGB1 release by AECs and HMGB1-induced excessive inflammatory response in RSV infection. RSV infection of AECs induces the biphasic release of HMGB1: early phase, which is necroptosis-independent but MLKL dependent, and late phase, which is necroptosis dependent. The early phase of HMGB1 release promotes the late phase of HMGB1 release via the activation of RAGE and initiation of RIPK1/RIPK3/MLKL phosphorylation. The TLR4/NF-κB pathway is also involved in HMGB1 release from AECs. RSV-induced ROS generation promoting the release of HMGB1 from cells likely occurs through the RIPK1/RIPK3/MLKL pathway and MSK1/NF-κB pathway. The release of HMGB1 induces an excessive inflammatory response that contributes to RSV pathogenesis