Endothelial-derived microparticles activates TLR4/JAK3/STAT3 pathway to induce acute lung injury

We previously reported that endothelial‐derived microparticles (EMP) could induce acute lung injury (ALI) and the mechanism is still not fully understood. Toll‐like receptor 4(TLR4) cascade has been considered to be involved in innate immune inflammation. As its downstream, janus kinases/signal transducers and activators of transcription (JAK/STAT), acts as a key signal pathway for immune responses. However, it remains unclear whether systemic circulating EMP could trigger TLR4‐pomoted JAK/STAT signaling contributing to ALI. EMP were isolated from human umbilical vein endothelial cells (HUVECs) stimulated with plasminogen activated inhibitor‐1. HUVECs were treated with/without different concentration of EMP. EMP induced inflammatory cytokines in cultured HUVECs. EMP could activated TLR4 and the downstream JAK3/STAT3 pathway. Silencing TLR4 inhibited the EMP‐induced JAK3/STAT3 pathway. EMP‐induced inflammatory response in plasma and bronchoalveolar lavage fluid, inflammatory cells infiltration. edema and JAK3/STAT3 pathway in the lung tissue, and ALI in C57BL6 mice. However, These effect induced by EMP were depressed in TLR4 −/− mice. Our data demonstrated that EMP induce ALI by activating TLR4/JAK3/STAT3 pathway to promote inflammatory response. Our findings present the novel mechanisms by which EMP induce ALI. Support or Funding Information This research was financially supported by the National Natural Science Foundation of China (Grants 81670392, 81600382, 81770241, 81830013, 81970363 and Distinguished Young Scholar Grant 81325001), 973 project (2009CB522104) and International Cooperation project (2015DFA31070) from the Ministry of Science and Technology of China, Guangdong Natural Science Fund Committee (Grant 2015A030312009), the Changjiang Scholars Program from the Ministry of Education of China, the Sun Yat‐sen University Clinical Research 5010 Program.