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

ABSTRACT: 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.

SUBMITTER: Saxton RA

PROVIDER: S-EPMC9132103 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Saxton Robert A RA Saxton Robert A RA Tsutsumi Naotaka N Su Leon L LL Abhiraman Gita C GC Mohan Kritika K Henneberg Lukas T LT Aduri Nanda G NG Gati Cornelius C Garcia K Christopher KC

Science (New York, N.Y.) 20210301 6535

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 desig ...[more]

PMID: 33737461

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Project description:Epstein Barr virus (EBV) is a gamma herpes virus associated with certain malignancies and autoimmune diseases. EBV maintains latency in B cells with occasional reactivation, in part by overcoming the host immune response with viral homologs of several human proteins. EBV interleukin 10 (vIL-10), a lytic phase protein, is a homolog of human IL-10 (hIL-10). The effect of vIL-10 on human monocytes, which are one of the first immune cells to respond to infection, is not known. To understand the role of vIL-10, monocytes from peripheral blood mononuclear cells were stimulated with hIL-10 or vIL-10. Human IL-10 stimulated STAT3 phosphorylation, which is required for suppression of inflammatory responses. However, vIL-10 induced significantly lower phosphorylation of STAT3 compared to hIL-10, and was less efficient in downregulating inflammatory genes. vIL-10 significantly reduced the expression of scavenger receptor CD163 on monocytes, suggesting inhibition of M2 polarization. Furthermore, uptake of apoptotic cells was reduced in vIL-10-stimulated monocytes compared to hIL-10-stimulated monocytes. A neutralizing antibody to IL-10R1 inhibited STAT3 phosphorylation induced by either hIL-10 or vIL-10, suggesting that vIL-10 signals through IL-10R1. Interestingly, vIL-10 suppressed hIL-10-induced STAT3 phosphorylation and inhibited upregulation of suppressors of inflammatory response by hIL-10. We further show that vIL-10 levels were significantly higher in plasma samples from systemic lupus erythematosus (SLE) patients compared to matched unaffected controls. vIL-10 levels did not correlate with hIL-10 levels, but were associated with levels of IgA antibodies to EBV viral capsid antigen, which is an indirect measure of viral reactivation. We propose that the suppression of hIL-10- induced anti-inflammatory genes by vIL-10, together with an increase in inflammatory gene expression, may overcome the anti-inflammatory effects of hIL-10 and exacerbate autoimmune responses in systemic autoimmune diseases.

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

Publications

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

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