CC chemokine receptor 6 (CCR6) in the pathogenesis of systemic lupus erythematosus

Lee, Adrian Y S; Körner, Heinrich

doi:10.1111/imcb.12375

Cited by 11 publications

(6 citation statements)

References 76 publications

(198 reference statements)

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“…In the patient, the CD4 + CD45R0 + CCR6 − helper T cell–derived CCR4 + CXCR3 − helper type 2 (T H 2) subset was decreased, reflecting lupus disease activity (fig. S6D) ( 31 , 32 ). CD56 + CD57 + mature natural killer cells were reduced and CD16 + HLA-DR + proinflammatory monocytes were increased in the patient (fig.…”

Section: Resultsmentioning

confidence: 99%

Disrupted degradative sorting of TLR7 is associated with human lupus

Mishra,

Schlack-Leigers,

Lim

et al. 2024

Sci. Immunol.

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Hyperactive TLR7 signaling has long been appreciated as driver of autoimmune disease in mouse models. Recently, gain-of-function mutations in TLR7 were identified as a monogenic cause of human lupus. TLR7 is an intracellular transmembrane receptor, sensing RNA breakdown products within late endosomes. Here, we show that endosome dysfunction leads to unrestricted TLR7 signaling and is associated with human lupus. The late endosomal BORC complex together with the small GTPase Arl8b controls intracellular TLR7 levels by regulating receptor turnover. This requires a direct interaction between the TLR7-associated trafficking factor Unc93b1 and Arl8b. We identified an UNC93B1 mutation in a patient with childhood-onset lupus, which results in reduced BORC interaction and endosomal TLR7 accumulation. Therefore, a failure to control TLR7 turnover is sufficient to break immunological tolerance to nucleic acids. Our results highlight the importance of an intact endomembrane system in preventing pathological TLR7 signaling and autoimmune disease.

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Section: Resultsmentioning

confidence: 99%

Disrupted degradative sorting of TLR7 is associated with human lupus

Mishra,

Schlack-Leigers,

Lim

et al. 2024

Sci. Immunol.

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“…Higher percentages of CCR6+ T helper cells have been found in patients with systemic lupus erythematosus (SLE), especially in lupus nephritis. The receptor expression is correlated with disease activity and serological markers of disease severity [ 86 , 87 ]. However, more assays are still needed to determine the role of the CCR6/CCL20 axis in SLE.…”

Section: Diseases Associated With Ccr6mentioning

confidence: 99%

CCR6 as a Potential Target for Therapeutic Antibodies for the Treatment of Inflammatory Diseases

Gómez-Melero

Caballero-Villarraso

2023

Antibodies

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The CC chemokine receptor 6 (CCR6) is a G protein-coupled receptor (GPCR) involved in a wide range of biological processes. When CCR6 binds to its sole ligand CCL20, a signaling network is produced. This pathway is implicated in mechanisms related to many diseases, such as cancer, psoriasis, multiple sclerosis, HIV infection or rheumatoid arthritis. The CCR6/CCL20 axis plays a fundamental role in immune homeostasis and activation. Th17 cells express the CCR6 receptor and inflammatory cytokines, including IL-17, IL-21 and IL-22, which are involved in the spread of inflammatory response. The CCL20/CCR6 mechanism plays a crucial role in the recruitment of these pro-inflammatory cells to local tissues. To date, there are no drugs against CCR6 approved, and the development of small molecules against CCR6 is complicated due to the difficulty in screenings. This review highlights the potential as a therapeutic target of the CCR6 receptor in numerous diseases and the importance of the development of antibodies against CCR6 that could be a promising alternative to small molecules in the treatment of CCR6/CCL20 axis-related pathologies.

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“…10 Therefore, antagonizing CCR6 could represent an effective therapy for autoantibody-driven autoimmune diseases, such as systemic lupus erythematosus. 11 A representative selection of CCR6 antagonists reported in the literature from academia and industry is illustrated in Figure 1. Only the small-molecule PF-07054894 is currently in early clinical trials for intestinal bowel disease.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of the Clinical Candidate IDOR-1117-2520: A Potent and Selective Antagonist of CCR6 for Autoimmune Diseases

Meyer,

Croxford,

Gnerre

et al. 2024

J. Med. Chem.

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Migration of immune cells to sites of inflammation is a critical step in the body’s response to infections but also during autoimmune flares. Chemokine receptors, members of the GPCR receptors, are instrumental in directing specific cell types to their target organs. Herein, we describe a highly potent small molecule antagonist of the chemokine receptor CCR6, which came out of fine-tuned structural elaborations from a proprietary HTS hit. Three main issues in the parent chemical series–cytotoxicity, phototoxicity, and hERG, were successfully solved. Biological characterization demonstrated that compound 45 (IDOR-1117-2520) is a selective and insurmountable antagonist of CCR6. In vivo proof-of-mechanism studies in a mouse lung inflammation model using a representative compound from the chemical class of 45 confirmed that the targeted CCR6+ cells were efficiently inhibited from migrating into the bronchoalveoli. Finally, ADMET and physicochemical properties were well balanced and the preclinical package warranted progress in the clinic.

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CC chemokine receptor 6 (CCR6) in the pathogenesis of systemic lupus erythematosus

Cited by 11 publications

References 76 publications

Disrupted degradative sorting of TLR7 is associated with human lupus

Disrupted degradative sorting of TLR7 is associated with human lupus

CCR6 as a Potential Target for Therapeutic Antibodies for the Treatment of Inflammatory Diseases

Discovery of the Clinical Candidate IDOR-1117-2520: A Potent and Selective Antagonist of CCR6 for Autoimmune Diseases

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