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Anti‐proinflammatory cytokine therapies against interleukin (IL)‐6, tumor necrosis factor (TNF)‐α, and IL‐1 are major advancements in treating inflammatory diseases, especially rheumatoid arthritis. Such therapies are mainly performed by injection of antibodies against cytokines or cytokine receptors. We initially found that the glycolytic inhibitor 2‐deoxy‐d‐glucose (2‐DG), a simple monosaccharide, attenuated cellular responses to IL‐6 by inhibiting N‐linked glycosylation of the IL‐6 receptor gp130. Aglycoforms of gp130 did not bind to IL‐6 or activate downstream intracellular signals that included Janus kinases. 2‐DG completely inhibited dextran sodium sulfate‐induced colitis, a mouse model for inflammatory bowel disease, and alleviated laminarin‐induced arthritis in the SKG mouse, an experimental model for human rheumatoid arthritis. These diseases have been shown to be partially dependent on IL‐6. We also found that 2‐DG inhibited signals for other proinflammatory cytokines such as TNF‐α, IL‐1β, and interferon ‐γ, and accordingly, prevented death by another inflammatory disease, lipopolysaccharide (LPS) shock. Furthermore, 2‐DG prevented LPS shock, a model for a cytokine storm, and LPS‐induced pulmonary inflammation, a model for acute respiratory distress syndrome of coronavirus disease 2019 (COVID‐19). These results suggest that targeted therapies that inhibit cytokine receptor glycosylation are effective for treatment of various inflammatory diseases. The glycolytic inhibitor 2‐deoxy‐D‐glucose attenuated cellular responses to proinflammatory cytokines by inhibiting N‐linked glycosylation of their receptors and alleviated the signs and symptoms of mouse models for inflammatory bowel disease, rheumatoid arthritis, cytokine storm, and acute respiratory distress syndrome.

Interferons (IFNs) are critical soluble factors in the immune system and are composed of three types, (I, II and III) that utilize different receptor complexes IFN-αR1/IFN-αR2, IFN-γR1/IFN-γR2, and IFN-λR1/IL-10R2, respectively. Here we identify IFN-υ from the genomic sequences of vertebrates. The members of class II cytokine receptors, IFN-υR1 and IL-10R2, are identified as the receptor complex of IFN-υ, and are associated with IFN-υ stimulated gene expression and antiviral activity in zebrafish ( Danio rerio ) and African clawed frog ( Xenopus laevis ). IFN-υ and IFN-υR1 are separately located at unique and highly conserved loci, being distinct from all other three-type IFNs. IFN-υ and IFN-υR1 are phylogenetically clustered with class II cytokines and class II cytokine receptors, respectively. Therefore, the finding of this IFN ligand-receptor system may be considered as a type IV IFN, in addition to the currently recognized three types of IFNs in vertebrates. Interferons are critical soluble components of the inflammatory process and are composed of three types with associated receptor complexes. Here the authors identify and characterise the type IV interferon, IFN-υ, and identify its associated receptors, denote functionality during in vivo infection and ascertain its genomic localisation.

The heterodimeric cytokine IL-27 consists of the subunits p28 and EBI3. Hunter and colleagues demonstrate that p28 acting alone can inhibit the signaling of many cytokines by interfering with the common receptor gp130. The heterodimeric cytokine interleukin 27 (IL-27) signals through the IL-27Rα subunit of its receptor, combined with gp130, a common receptor chain used by several cytokines, including IL-6. Notably, the IL-27 subunits p28 (IL-27p28) and EBI3 are not always expressed together, which suggests that they may have unique functions. Here we show that IL-27p28, independently of EBI3, antagonized cytokine signaling through gp130 and IL-6-mediated production of IL-17 and IL-10. Similarly, the ability to generate antibody responses was dependent on the activity of gp130-signaling cytokines. Mice transgenic for expression of IL-27p28 showed a substantial defect in the formation of germinal centers and antibody production. Thus, IL-27p28, as a natural antagonist of gp130-mediated signaling, may be useful as a therapeutic for managing inflammation mediated by cytokines that signal through gp130.

Cytokine receptor-like factor 3 (CRLF3) has an extended evolutionary history, which has been conserved across metazoan species. It consists of several structural elements, notably including a fibronectin type 3 (FBNIII) domain containing a WSXWS motif that is synonymous with so-called class I cytokine receptors present throughout bilaterial species, and a proposed spl1 and ryanodine receptor (SPRY) domain that represents a widespread protein–protein interaction module. The function of CRLF3 has remained enigmatic, but several recent investigations have revealed critical insights into its biological roles. These studies suggest that CRLF3 principally functions in neural and hematopoietic cells, where it plays critical and diverse roles in the development and function of specific cell populations. Disruption of CRLF3 has also been associated with several human diseases, mainly associated with these same lineages but also including malignancy. The mechanisms by which CRLF3 exerts these diverse effects remain uncertain, although a number of potential options have emerged.

Activating Janus kinase (JAK) and signal transducer and activator of transcription (STAT) mutations have been discovered in many T-cell malignancies, including anaplastic lymphoma kinase (ALK)⁻ anaplastic large cell lymphomas (ALCLs). However, such mutations occur in a minority of patients. To investigate the clinical application of targeting JAK for ALK− ALCL, we treated ALK− cell lines of various histological origins with JAK inhibitors. Interestingly, most exogenous cytokine-independent cell lines responded to JAK inhibition regardless of JAK mutation status. JAK inhibitor sensitivity correlated with the STAT3 phosphorylation status of tumor cells. Using retroviral shRNA knockdown, we have demonstrated that these JAK inhibitor-sensitive cells are dependent on both JAK1 and STAT3 for survival. JAK1 and STAT3 gain-of-function mutations were found in some, but not all, JAK inhibitor-sensitive cells. Moreover, the mutations alone cannot explain the JAK1/STAT3 dependency, given that wild-type JAK1 or STAT3 was sufficient to promote cell survival in the cells that had either JAK1or STAT3 mutations. To investigate whether other mechanisms were involved, we knocked down upstream receptors GP130 or IL-2Rγ. Knockdown of GP130 or IL-2Rγ induced cell death in selected JAK inhibitor-sensitive cells. High expression levels of cytokines, including IL-6, were demonstrated in cell lines as well as in primary ALK− ALCL tumors. Finally, ruxolitinib, a JAK1/2 inhibitor, was effective in vivo in a xenograft ALK− ALCL model. Our data suggest that cytokine receptor signaling is required for tumor cell survival in diverse forms of ALK− ALCL, even in the presence of JAK1/STAT3 mutations. Therefore, JAK inhibitor therapy might benefit patients with ALK− ALCL who are phosphorylated STAT3⁺.

Targeted degradation of cell surface and extracellular proteins via lysosomal delivery is an important means to modulate extracellular biology. However, these approaches have limitations due to lack of modularity, ease of development, restricted tissue targeting and applicability to both cell surface and extracellular proteins. We describe a lysosomal degradation strategy, termed cytokine receptor-targeting chimeras (KineTACs), that addresses these limitations. KineTACs are fully genetically encoded bispecific antibodies consisting of a cytokine arm, which binds its cognate cytokine receptor, and a target-binding arm for the protein of interest. We show that KineTACs containing the cytokine CXCL12 can use the decoy recycling receptor, CXCR7, to target a variety of target proteins to the lysosome for degradation. Additional KineTACs were designed to harness other CXCR7-targeting cytokines, CXCL11 and vMIPII, and the interleukin-2 (IL-2) receptor-targeting cytokine IL-2. Thus, KineTACs represent a general, modular, selective and simple genetically encoded strategy for inducing lysosomal delivery of extracellular and cell surface targets with broad or tissue-specific distribution. KineTACs are modular bispecific antibodies for degradation of extracellular and cell-surface proteins.

Cytokines are secreted signalling proteins that play essential roles in the initiation, maintenance and resolution of immune responses. Although the unique ability of cytokines to control immune function has garnered clinical interest in the context of cancer, autoimmunity and infectious disease, the use of cytokine-based therapeutics has been limited. This is due, in part, to the ability of cytokines to act on many cell types and impact diverse biological functions, resulting in dose-limiting toxicity or lack of efficacy. Recent studies combining structural biology, protein engineering and receptor pharmacology have unlocked new insights into the mechanisms of cytokine receptor activation, demonstrating that many aspects of cytokine function are highly tunable. Here, we discuss the pharmacological principles underlying these efforts to overcome cytokine pleiotropy and enhance the therapeutic potential of this important class of signalling molecules.The exploitation of cytokines for therapeutic use has been limited by their pleiotropic activity, which has contributed to dose-limiting toxicity and lack of efficacy. Here, Garcia and colleagues discuss how recent insights from structural biology, protein engineering and receptor pharmacology have unveiled strategies to overcome cytokine pleiotropy and enable the design of new and improved cytokine-based therapeutics.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has highlighted the urgent need to rapidly develop therapeutic strategies for such emerging viruses without effective vaccines or drugs. Here, we report a decoy nanoparticle against COVID-19 through a powerful two-step neutralization approach: virus neutralization in the first step followed by cytokine neutralization in the second step. The nanodecoy, made by fusing cellular membrane nanovesicles derived from human monocytes and genetically engineered cells stably expressing angiotensin converting enzyme II (ACE2) receptors, possesses an antigenic exterior the same as source cells. By competing with host cells for virus binding, these nanodecoys effectively protect host cells from the infection of pseudoviruses and authentic SARS-CoV-2. Moreover, relying on abundant cytokine receptors on the surface, the nanodecoys efficiently bind and neutralize inflammatory cytokines including interleukin 6 (IL-6) and granulocyte–macrophage colony-stimulating factor (GM-CSF), and significantly suppress immune disorder and lung injury in an acute pneumonia mouse model. Our work presents a simple, safe, and robust antiviral nanotechnology for ongoing COVID-19 and future potential epidemics.

Altered cytokine levels and chronic low-grade inflammation contribute to metabolic dysfunction in obesity. The extent of cytokine changes and their impact on metabolic improvements after bariatric surgery have not been fully explored. To compare 76 circulating cytokines, chemokines, and secreted cytokine receptors in subjects with obesity and lean subjects and determine how these cytokines are altered by bariatric surgery. A total of 37 patients with obesity and 37 lean patients in a cross-sectional study at an academic medical center. We also investigated cytokine changes in 25 patients with obesity after bariatric surgery. Bariatric surgery (Roux-en-Y gastric bypass and vertical sleeve gastrectomy). Quantification of 76 circulating cytokines, chemokines, and secreted cytokine receptors. A total of 13 cytokines were significantly higher, and 4 lower, in patients with obesity relative to lean controls. Soluble vascular endothelial growth factor receptor 2 (sVEGFR2), soluble TNF receptor (sTNFR) 1, and sTNFR2 were positively correlated, and soluble receptor for advanced glycation end-products was inversely correlated, with weight and body mass index. sTNFR2 was positively correlated with fasting glucose, homeostatic model assessment of insulin resistance, and hemoglobin A1c. After bariatric surgery, adiponectin increased, and leptin decreased. Elevated sVEGFR2 levels in patients with obesity were decreased (P = 0.01), whereas reduced chemokine (C-X-C motif) ligand (CXCL) 12 levels in patients with obesity increased (P = 0.03) after surgery. Patients with higher soluble interleukin receptor (sIL) 1R2 and sIL-6R levels before surgery had greater weight loss after surgery (P < 0.05). We demonstrate that chemokine (C-C motif) ligand (CCL) 14, sVEGFR2, and platelet-derived growth factor BB are elevated in obesity, and CXCL12, CCL11, and CCL27 are lower in obesity. We found clinically concordant directionality between lean and patients with obesity and before vs after surgery for six cytokines, suggesting that bariatric surgery shifted the cytokine profiles of patients with obesity toward that of lean controls.

Cytokine release syndrome (CRS), commonly known as cytokine storm, is an acute systemic inflammatory response that is a significant global health threat. Interleukin-6 (IL-6) and interleukin-1 (IL-1) are key pro-inflammatory cytokines involved in CRS and are hence critical therapeutic targets. Current antagonists, such as tocilizumab and anakinra, target IL-6R/IL-1R but have limitations due to their long half-life and systemic anti-inflammatory effects, making them less suitable for acute or localized treatments. Here we present the de novo design of small protein antagonists that prevent IL-1 and IL-6 from interacting with their receptors to activate signaling. The designed proteins bind to the IL-6R, GP130 (an IL-6 co-receptor), and IL-1R1 receptor subunits with binding affinities in the picomolar to low-nanomolar range. X-ray crystallography studies reveal that the structures of these antagonists closely match their computational design models. In a human cardiac organoid disease model, the IL-1R antagonists demonstrated protective effects against inflammation and cardiac damage induced by IL-1β. These minibinders show promise for administration via subcutaneous injection or intranasal/inhaled routes to mitigate acute cytokine storm effects. Here, the authors computationally designed and produced small protein antagonists to target IL-6 and IL-1β signaling to develop modulators of CRS.