Abstract
Endothelial dysfunction is a primary pathophysiological change in sepsis. Macrophages are known to interact with vascular endothelial cells during the development of sepsis. Recently, drug delivery based on engineered macrophages was reported as an alternative approach for the management of diseases. Interleukin-10 (IL10) is a well-known anti-inflammatory cytokine, which reduces inflammation and inhibits dysfunction of endothelial cells caused by sepsis. It is currently poorly understood whether genetically modified macrophages with overexpression of IL10 are able to restore endothelial integrity and function at the cellular level. In this study, we used lentiviral vectors to construct RAW264.7 macrophages engineered to overexpress IL10 (IL10-eM) and investigated the effects of the IL10-eM supernatant on LPS-induced endothelial dysfunction using a noncontact coculture system. We found that cotreatment with IL10-eM supernatant significantly attenuates the effects of LPS-induced dysfunction of endothelial cells, including endothelial inflammatory response, endothelial permeability, and apoptosis. In addition, we discovered that LPS-induced downregulation of VE-cadherin and high production of reactive oxygen species were significantly attenuated upon IL10-eM exposure. Furthermore, upregulation of IL6, TNFα, and Bax was decreased after treatment of cells with IL10-eM supernatant. These results demonstrated that supernatant from engineered macrophages genetically modified with IL10 can effectively protect endothelial cells against LPS-induced dysfunction in vitro, suggesting that exosomes from such engineered macrophages may have therapeutic effects against sepsis.