ACKR2 limits skin fibrosis and hair loss through IFN‐β

Butenko, Sergei; Jashar, Nofar Ben; Sheffer, Tsofiya; Sabo, Edmond; Schif-Zuck, Sagie; Ariel, Amiram

doi:10.1096/fj.202002395rr

Cited by 8 publications

(4 citation statements)

References 62 publications

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“…Additionally, recent knockout studies in ACKR2 −/− mice revealed the importance of interferon-beta in the rescue of collagen organization and hair loss. 22 However, due to alopecia reports in the literature and prescription label for the interferons, further exploration is warranted.…”

Section: Discussionmentioning

confidence: 99%

Alopecia in Multiple Sclerosis Patients Treated with Disease Modifying Therapies

Porwal

Salter

Patel

et al. 2022

J Cent Nerv Syst Dis

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BACKGROUND There is currently limited literature addressing the reporting of alopecia in multiple sclerosis (MS) patients treated with disease-modifying therapies (DMTs). Anecdotal reports of hair thinning from patients on various DMTs prompted further investigation of a large database. OBJECTIVE To analyze total reports, source of reporting, age distribution, and sex distribution of alopecia associated with DMTs. METHODS FDA Adverse Event Reporting System (FAERS) public dashboard and OpenFDA database were analyzed for alopecia reports between January 1, 2009, and June 30, 2020, attributed to usage in MS of FDA approved DMTs. The main outcomes included total reports for each drug, age, sex distribution, and reporting source. OpenFDA data was used for statistical analyses including reporting odds ratios (ROR) and information components. RESULTS 8759 alopecia reports were identified among 44 114 adverse events in skin and subcutaneous tissue disorders (19.9%). 3701 (42.3%) with teriflunomide, 1675 (19.1%) with dimethyl fumarate, 985 (11.2%) with natalizumab, 926 (10.6%) with fingolimod, 659 (7.5%) with interferon beta-1a, 257 (2.9%) with glatiramer acetate, 243 (2.8%) with ocrelizumab, 124 (1.4%) with interferon beta-1b, 117 (1.3%) with alemtuzumab, 36 (.4%) with siponimod, 24 (.3%) with cladribine, and 12 (.1%) with rituximab. Reports were mostly made by patients (78.3%) and highest in fifth and sixth decades of life. OpenFDA analyses showed increased ROR (ROR 95% confidence interval) of alopecia in females with teriflunomide (18.00, 17.12-18.93), alemtuzumab (1.43, 1.16-1.76), dimethyl fumarate (1.26, 1.18-1.34), and ocrelizumab (1.28, 1.11-1.49). Increased ROR in males was associated with teriflunomide (24.65, 20.72-29.31). CONCLUSION We identified many reports of alopecia for DMTs in addition to teriflunomide. Within the limitations of the database, increased RORs of alopecia were observed for females treated with alemtuzumab, dimethyl fumarate, and ocrelizumab. The source of reporting was largely driven by female patients. Possible alopecia, even if transient, should be considered during patient education when starting DMTs.

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Section: Discussionmentioning

confidence: 99%

Alopecia in Multiple Sclerosis Patients Treated with Disease Modifying Therapies

Porwal

Salter

Patel

et al. 2022

J Cent Nerv Syst Dis

View full text Add to dashboard Cite

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“…The relationship with VEGFA-VEGFR signaling is consistent with previously reported observations on ACKR2 expression in lung endothelial cells ( Hansell et al, 2020 ). Furthermore, TGFβ signaling, which has known influences on ACKR2 expression ( McKimmie, et al 2013 ) plays a role in skin fibrosis ( Butenko, Ben Jashar et al, 2021 ). The reported role of ACKR2 in the systemic regulation of glucose tolerance, accompanied by reduced insulin secretion and increased whole body insulin sensitivity ( Zheng, et al 2016 , Fioravante et al 2019 ) is consistent with the identified enrichment in the insulin signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Phosphoproteomic mapping of CCR5 and ACKR2 signaling properties

Vacchini

Maffioli

Silvestre

et al. 2022

Front. Mol. Biosci.

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ACKR2 is an atypical chemokine receptor which is structurally uncoupled from G proteins and is unable to activate signaling pathways used by conventional chemokine receptors to promote cell migration. Nonetheless, ACKR2 regulates inflammatory and immune responses by shaping chemokine gradients in tissues via scavenging inflammatory chemokines. To investigate the signaling pathways downstream to ACKR2, a quantitative SILAC-based phosphoproteomic analysis coupled with a systems biology approach with network analysis, was carried out on a HEK293 cell model expressing either ACKR2 or its conventional counterpart CCR5. The model was stimulated with the common agonist CCL3L1 for short (3 min) and long (30 min) durations. As expected, many of the identified proteins are known to participate in conventional signal transduction pathways and in the regulation of cytoskeleton dynamics. However, our analyses revealed unique phosphorylation and network signatures, suggesting roles for ACKR2 other than its scavenger activity. In conclusion, the mapping of phosphorylation events at a holistic level indicated that conventional and atypical chemokine receptors differ in signaling properties. This provides an unprecedented level of detail in chemokine receptor signaling and identifying potential targets for the regulation of ACKR2 and CCR5 function.

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“…After bleomycin exposure, Ifnb –/– mice showed increased pro-fibrotic indices. There is evidence to indicate that ACKR2 is one of the key players in preventing chronic inflammation-induced skin scarring caused by promoting IFN-β production ( 117 ).…”

Section: The Role Of Ackr2 In Diseasesmentioning

confidence: 99%

The Role of Atypical Chemokine Receptor D6 (ACKR2) in Physiological and Pathological Conditions; Friend, Foe, or Both?

et al. 2022

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Chemokines exert crucial roles in inducing immune responses through ligation to their canonical receptors. Besides these receptors, there are other atypical chemokine receptors (ACKR1–4) that can bind to a wide range of chemokines and carry out various functions in the body. ACKR2, due to its ability to bind various CC chemokines, has attracted much attention during the past few years. ACKR2 has been shown to be expressed in different cells, including trophoblasts, myeloid cells, and especially lymphoid endothelial cells. In terms of molecular functions, ACKR2 scavenges various inflammatory chemokines and affects inflammatory microenvironments. In the period of pregnancy and fetal development, ACKR2 plays a pivotal role in maintaining the fetus from inflammatory reactions and inhibiting subsequent abortion. In adults, ACKR2 is thought to be a resolving agent in the body because it scavenges chemokines. This leads to the alleviation of inflammation in different situations, including cardiovascular diseases, autoimmune diseases, neurological disorders, and infections. In cancer, ACKR2 exerts conflicting roles, either tumor-promoting or tumor-suppressing. On the one hand, ACKR2 inhibits the recruitment of tumor-promoting cells and suppresses tumor-promoting inflammation to blockade inflammatory responses that are favorable for tumor growth. In contrast, scavenging chemokines in the tumor microenvironment might lead to disruption in NK cell recruitment to the tumor microenvironment. Other than its involvement in diseases, analyzing the expression of ACKR2 in body fluids and tissues can be used as a biomarker for diseases. In conclusion, this review study has tried to shed more light on the various effects of ACKR2 on different inflammatory conditions.

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ACKR2 limits skin fibrosis and hair loss through IFN‐β

Cited by 8 publications

References 62 publications

Alopecia in Multiple Sclerosis Patients Treated with Disease Modifying Therapies

Alopecia in Multiple Sclerosis Patients Treated with Disease Modifying Therapies

Phosphoproteomic mapping of CCR5 and ACKR2 signaling properties

The Role of Atypical Chemokine Receptor D6 (ACKR2) in Physiological and Pathological Conditions; Friend, Foe, or Both?

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