Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10

Saxton, Robert A.; Tsutsumi, Naotaka; Su, Leon L.; Abhiraman, Gita C.; Mohan, Kritika; Henneberg, Lukas T.; Aduri, Nanda G.; Gati, Cornelius; Garcia, K. Christopher

doi:10.1126/science.abc8433

Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10

Journal Article · Thu Mar 18 00:00:00 EDT 2021 · Science

DOI:https://doi.org/10.1126/science.abc8433· OSTI ID:1771371

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Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA., Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA., Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA., Biosciences Division, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA.
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA., Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA., Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.

Interleukin-10 (IL-10) is an immunoregulatory cytokine with both anti-inflammatory and immunostimulatory properties and is frequently dysregulated in disease. We used a structure-based approach to deconvolute IL-10 pleiotropy by determining the structure of the IL-10 receptor (IL-10R) complex by cryo–electron microscopy at a resolution of 3.5 angstroms. The hexameric structure shows how IL-10 and IL-10Rα form a composite surface to engage the shared signaling receptor IL-10Rβ, enabling the design of partial agonists. IL-10 variants with a range of IL-10Rβ binding strengths uncovered substantial differences in response thresholds across immune cell populations, providing a means of manipulating IL-10 cell type selectivity. Some variants displayed myeloid-biased activity by suppressing macrophage activation without stimulating inflammatory CD8 ⁺ T cells, thereby uncoupling the major opposing functions of IL-10. These results provide a mechanistic blueprint for tuning the pleiotropic actions of IL-10.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); Stanford Medical Scientist Training Program; USDOE; USDOE Laboratory Directed Research and Development (LDRD) Program; USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 1771371

Alternate ID(s):: OSTI ID: 1781077

Journal Information:: Science, Journal Name: Science Journal Issue: 6535 Vol. 371; ISSN 0036-8075

Publisher:: American Association for the Advancement of Science (AAAS)Copyright Statement

Country of Publication:: United States

Language:: English

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