期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：44
页码：E4753-E4761
DOI：10.1073/pnas.1415006111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceInability of the body to contain infections may lead to collateral organ damage resulting from unchecked innate immune responses. Here we investigated the chemical signals produced by immune cells to expedite clearance of bacteria and promote organ repair and tissue regeneration. We identified molecules produced during self-limited infections and in human milk that promote clearance of bacteria as well as accelerate tissue regeneration. In addition, these molecules also protected organs from exuberant inflammatory responses by limiting select white blood cell recruitment and up-regulating the expression of proteins involved in tissue repair. Therefore, these results identify new resolution moduli that regulate phagocytes to clear bacteria and activate the regeneration milieu. Upon infection and inflammation, tissue repair and regeneration are essential in reestablishing function. Here we identified potent molecules present in self-limited infectious murine exudates, regenerating planaria, and human milk as well as macrophages that stimulate tissue regeneration in planaria and are proresolving. Characterization of their physical properties and isotope tracking indicated that the bioactive structures contained docosahexaenoic acid and sulfido-conjugate (SC) of triene double bonds that proved to be 13-glutathionyl, 14-hydroxy-docosahexaenoic acid (SCI) and 13-cysteinylglycinyl, 14-hydroxy-docosahexaenoic acid (SCII). These molecules rescued Escherichia coli infection-mediated delay in tissue regeneration in planaria, improving regeneration intervals from [~]4.2 to [~]3.7 d. Administration of SCs protected mice from second-organ reflow injury, promoting repair via limiting neutrophil infiltration, up-regulating Ki67, and Roof plate-specific spondin 3. At nanomolar potencies these conjugates also resolved E. coli infections by limiting neutrophil infiltration and stimulating bacterial phagocytosis and clearance as well as efferocytosis of apoptotic cells. Together, these findings identify previously undescribed conserved chemical signals and pathways in planaria, mouse, and human tissues that enhance host responses to contain infections, stimulate resolution of inflammation, and promote the restoration of function.
