A strategy to discover decoy chemokine ligands with an anti-inflammatory activity

Abboud, Dayana; Daubeuf, François; Tuan, Quoc; Utard, Valérie; Villa, Pascal; Haiech, Jacques; Bron, Dominique; Hibert, Marcel; Bernard, Philippe; Galzi, Jean‐Luc; Frossard, Nelly

doi:10.1038/srep14746

Cited by 20 publications

(39 citation statements)

References 52 publications

(64 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To our knowledge the importance of B cell expressed CCR4 in the human germinal center response has however not previously been investigated. These findings have important clinical implications given that high affinity neutraligands have been developed for CCL22 and CCL17, and these inhibit both the chemokine-induced intracellular calcium responses and CCR4 endocytosis in vitro , and inflammation in vivo in a murine model of asthma58. Of relevance to atopic dermatitis, the synthetic molecule 5,6-dihydroergosteol-glucoside (DHE-Glc) has also been shown to suppress TNF-α/IFN-γ-induced expression of CCL17 and CCL22 in the human keratinocyte cell line HaCaT, and attenuate levels of CCL22, CCL17 and IgE in a mouse model of atopic dermatitis as well as improve skin inflammatory symptoms59.…”

Section: Discussionmentioning

confidence: 92%

Global gene regulation during activation of immunoglobulin class switching in human B cells

Zhang

Fear

Willis‐Owen

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Immunoglobulin class switch recombination (CSR) to IgE is a tightly regulated process central to atopic disease. To profile the B-cell transcriptional responses underlying the activation of the germinal centre activities leading to the generation of IgE, naïve human B-cells were stimulated with IL-4 and anti-CD40. Gene expression and alternative splicing were profiled over 12 days using the Affymetrix Human Exon 1.0 ST Array. A total of 1,399 genes, forming 13 temporal profiles were differentially expressed. CCL22 and CCL17 were dramatically induced but followed a temporal trajectory distinct from classical mediators of isotype switching. AICDA, NFIL3, IRF4, XBP1 and BATF3 shared a profile with several genes involved in innate immunity, but with no recognised role in CSR. A transcription factor BHLHE40 was identified at the core of this profile. B-cell activation was also accompanied by variation in exon retention affecting >200 genes including CCL17. The data indicate a circadian component and central roles for the Th2 chemokines CCL22 and CCL17 in the activation of CSR.

show abstract

Section: Discussionmentioning

confidence: 92%

Global gene regulation during activation of immunoglobulin class switching in human B cells

Zhang

Fear

Willis‐Owen

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…In vitro experiments have indicated that these neutraligands can inhibit CCL17- or CCL22-induced intracellular calcium responses, CCR4 endocytosis, and human T cell migration. Furthermore, in an in vivo experiment, neutraligands inhibited inflammation in a murine model of asthma [ 114 ].…”

Section: Therapeutic Targeting Of Ccl17/ccl22 and Ccr4mentioning

confidence: 99%

The C-C Chemokines CCL17 and CCL22 and Their Receptor CCR4 in CNS Autoimmunity

Scheu

Ali

Ruland

et al. 2017

IJMS

109

105

View full text Add to dashboard Cite

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). It affects more than two million people worldwide, mainly young adults, and may lead to progressive neurological disability. Chemokines and their receptors have been shown to play critical roles in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a murine disease model induced by active immunization with myelin proteins or transfer of encephalitogenic CD4+ T cells that recapitulates clinical and neuropathological features of MS. Chemokine ligand-receptor interactions orchestrate leukocyte trafficking and influence multiple pathophysiological cellular processes, including antigen presentation and cytokine production by dendritic cells (DCs). The C-C class chemokines 17 (CCL17) and 22 (CCL22) and their C-C chemokine receptor 4 (CCR4) have been shown to play an important role in homeostasis and inflammatory responses. Here, we provide an overview of the involvement of CCR4 and its ligands in CNS autoimmunity. We review key clinical studies of MS together with experimental studies in animals that have demonstrated functional roles of CCR4, CCL17, and CCL22 in EAE pathogenesis. Finally, we discuss the therapeutic potential of newly developed CCR4 antagonists and a humanized anti-CCR4 antibody for treatment of MS.

show abstract

“…“Treat-to-target” strategies hope to avoid the systemic side effects of steroids. It is also known that pathogens manipulate the human immune system, such as encoding for CKs, CKRs, soluble proteins, or extracellular matrix-mimicking components ( 177 ). All of these decoy proteins prevent CK binding to GAGs and extracellular CK gradients that attract circulating immune cells or CK binding to its cognate receptor ( 177 ).…”

Section: Targeting Cks or Other Cytokinesmentioning

confidence: 99%

Advances in Biomarker-Guided Therapy for Pediatric- and Adult-Onset Neuroinflammatory Disorders: Targeting Chemokines/Cytokines

Pranzatelli

2018

Front. Immunol.

View full text Add to dashboard Cite

The concept and recognized components of “neuroinflammation” are expanding at the intersection of neurobiology and immunobiology. Chemokines (CKs), no longer merely necessary for immune cell trafficking and positioning, have multiple physiologic, developmental, and modulatory functionalities in the central nervous system (CNS) through neuron–glia interactions and other mechanisms affecting neurotransmission. They issue the “help me” cry of neurons and astrocytes in response to CNS injury, engaging invading lymphoid cells (T cells and B cells) and myeloid cells (dendritic cells, monocytes, and neutrophils) (adaptive immunity), as well as microglia and macrophages (innate immunity), in a cascade of events, some beneficial (reparative), others destructive (excitotoxic). Human cerebrospinal fluid (CSF) studies have been instrumental in revealing soluble immunobiomarkers involved in immune dysregulation, their dichotomous effects, and the cells—often subtype specific—that produce them. CKs/cytokines continue to be attractive targets for the pharmaceutical industry with varying therapeutic success. This review summarizes the developing armamentarium, complexities of not compromising surveillance/physiologic functions, and insights on applicable strategies for neuroinflammatory disorders. The main approach has been using a designer monoclonal antibody to bind directly to the chemo/cytokine. Another approach is soluble receptors to bind the chemo/cytokine molecule (receptor ligand). Recombinant fusion proteins combine a key component of the receptor with IgG1. An additional approach is small molecule antagonists (protein therapeutics, binding proteins, and protein antagonists). CK neutralizing molecules (“neutraligands”) that are not receptor antagonists, high-affinity neuroligands (“decoy molecules”), as well as neutralizing “nanobodies” (single-domain camelid antibody fragment) are being developed. Simultaneous, more precise targeting of more than one cytokine is possible using bispecific agents (fusion antibodies). It is also possible to inhibit part of a signaling cascade to spare protective cytokine effects. “Fusokines” (fusion of two cytokines or a cytokine and CK) allow greater synergistic bioactivity than individual cytokines. Another promising approach is experimental targeting of the NLRP3 inflammasome, amply expressed in the CNS and a key contributor to neuroinflammation. Serendipitous discovery is not to be discounted. Filling in knowledge gaps between pediatric- and adult-onset neuroinflammation by systematic collection of CSF data on CKs/cytokines in temporal and clinical contexts and incorporating immunobiomarkers in clinical trials is a challenge hereby set forth for clinicians and researchers.

show abstract

A strategy to discover decoy chemokine ligands with an anti-inflammatory activity

Cited by 20 publications

References 52 publications

Global gene regulation during activation of immunoglobulin class switching in human B cells

Global gene regulation during activation of immunoglobulin class switching in human B cells

The C-C Chemokines CCL17 and CCL22 and Their Receptor CCR4 in CNS Autoimmunity

Advances in Biomarker-Guided Therapy for Pediatric- and Adult-Onset Neuroinflammatory Disorders: Targeting Chemokines/Cytokines

Contact Info

Product

Resources

About