Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 44, Pages E4753-E4761Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1415006111
Keywords
regeneration; omega 3; leukocytes; inflammation; eicosanoids
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Funding
- National Institutes of Health [P01GM095467]
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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 similar to 4.2 to similar 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.
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