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.

Engineered IL‐10: A matter of affinity

“…Furthermore, IL‐10 can promote the cytotoxic function of CD8 + T cells by increasing interferon‐γ (IFN‐γ) and granzyme B production. Thus, the pro‐inflammatory activity of IL‐10 may have counteracted its therapeutic effects for the treatment of different inflammatory diseases 8,9 8,9 …”

“…Moreover, they conducted a comprehensive analysis of IL10/IL‐10Rβ interaction and STAT1/STAT3 activation on different cell populations, demonstrating that IL‐10 signaling is limited by the expression of its receptor. However, this could be compensated by enhancing its affinity for IL10Rβ 9 …”

“…6 IL-10 also inhibits the secretion of proinflammatory cytokines by T cells, 7 monocytes, and macrophages (Figure 1). 8,9 Despite its potent biological role, IL-10 administration has only elicited low/mild anti-inflammatory effects in several clinical trials to treat inflammatory bowel disease (IBD). 8 This low efficacy has been attributed to the difficulty for IL-10 to reach the target tissue.…”

Structure of the IL-27 quaternary receptor signaling complex

“…One such application may be to generate single agent IL-27 agonists by affinity maturing the interactions between p28 and its receptor subunit, as has been done recently to generate IL-6 which do not require IL-6Rα binding for efficient signaling (Martinez-Fabregas et al, 2019). Conversely, attenuating the affinity of p28 for IL-27Rα might be used to generate cell-type biased partial agonists with selective activity based on differences in IL-27Rα expression across cell-type and activation state (Villarino et al, 2005) as has been done for IL-2 (Glassman et al, 2021b), IL-10 (Saxton et al, 2021), and IL-12 (Glassman et al, 2021a).…”

Research-Based Product Innovation to Address Critical Unmet Needs of Patients with Inflammatory Bowel Diseases

“… 127 , 128 Supplementation with immunoregulatory cytokines is also conceptually appealing for IBD, though efforts in this arena have not yet been successful, potentially due to pleiotropic effects. 129 Significant development efforts have focused on IL-10, 130–132 transforming growth factor β, 133 , 134 and IL-22, which may restore epithelial integrity. 135 The larger point is that inflammation may evolve over the course of disease and that agents that neutralize a single cytokine may lose effectiveness over time, potentially requiring monitoring of disease activity and combination therapy to overcome treatment resistance.…”