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Pulmonary Cell NewsInterleukin-10 (IL-10) variants with a range of IL-10 receptor β binding strengths uncovered substantial differences in response thresholds across immune cell populations, providing a means of manipulating IL-10 cell type selectivity.
[Science]
1254621 {1254621:XYHW2DS5} apa 50 1 160330 https://www.stemcellsciencenews.com/wp-content/plugins/zotpress/
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%20Open%20in%20new%20tab%20Download%20Powerpoint%20Engineering%20IL-10.The%20structure%20of%20the%20IL-10%20receptor%20complex%20is%20shown%20on%20a%20cell%20surface%20with%20%5Cu201cengineers%5Cu201d%20depicted%20as%20welders%20making%20alterations%20to%20IL-10%20at%20the%20receptor-binding%20interface%20that%20was%20the%20focus%20of%20Saxton%20et%20al.ILLUSTRATION%3A%20ERIC%20SMITH%20AND%20CHRIS%20GARCIA%5CnInterleukin-10%20%28IL-10%29%20is%20an%20immunoregulatory%20cytokine%20with%20both%20anti-inflammatory%20and%20immunostimulatory%20properties%20and%20is%20frequently%20dysregulated%20in%20disease.%20We%20used%20a%20structure-based%20approach%20to%20deconvolute%20IL-10%20pleiotropy%20by%20determining%20the%20structure%20of%20the%20IL-10%20receptor%20%28IL-10R%29%20complex%20by%20cryo%5Cu2013electron%20microscopy%20at%20a%20resolution%20of%203.5%20angstroms.%20The%20hexameric%20structure%20shows%20how%20IL-10%20and%20IL-10R%5Cu03b1%20form%20a%20composite%20surface%20to%20engage%20the%20shared%20signaling%20receptor%20IL-10R%5Cu03b2%2C%20enabling%20the%20design%20of%20partial%20agonists.%20IL-10%20variants%20with%20a%20range%20of%20IL-10R%5Cu03b2%20binding%20strengths%20uncovered%20substantial%20differences%20in%20response%20thresholds%20across%20immune%20cell%20populations%2C%20providing%20a%20means%20of%20manipulating%20IL-10%20cell%20type%20selectivity.%20Some%20variants%20displayed%20myeloid-biased%20activity%20by%20suppressing%20macrophage%20activation%20without%20stimulating%20inflammatory%20CD8%2B%20T%20cells%2C%20thereby%20uncoupling%20the%20major%20opposing%20functions%20of%20IL-10.%20These%20results%20provide%20a%20mechanistic%20blueprint%20for%20tuning%20the%20pleiotropic%20actions%20of%20IL-10.%5CnThe%20cryo-EM%20structure%20of%20the%20IL-10%20receptor%20complex%20enables%20the%20rational%20design%20of%20myeloid-selective%20agonists.%5CnThe%20cryo-EM%20structure%20of%20the%20IL-10%20receptor%20complex%20enables%20the%20rational%20design%20of%20myeloid-selective%20agonists.%22%2C%22date%22%3A%222021%5C%2F03%5C%2F19%22%2C%22language%22%3A%22en%22%2C%22DOI%22%3A%2210.1126%5C%2Fscience.abc8433%22%2C%22ISSN%22%3A%220036-8075%2C%201095-9203%22%2C%22url%22%3A%22https%3A%5C%2F%5C%2Fscience.sciencemag.org%5C%2Fcontent%5C%2F371%5C%2F6535%5C%2Feabc8433%22%2C%22collections%22%3A%5B%5D%2C%22dateModified%22%3A%222021-03-19T19%3A58%3A20Z%22%7D%7D%5D%7D
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