ACKR2: An Atypical Chemokine Receptor Regulating Lymphatic Biology

Bonavita, Ornella; Poeta, Valeria Mollica; Setten, Elisa; Massara, Matteo; Bonecchi, Raffaella

doi:10.3389/fimmu.2016.00691

Cited by 23 publications

(24 citation statements)

References 55 publications

(66 reference statements)

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“…In mice lacking ACKR2, elevated presentation of inflammatory chemokines such as CCL2 on peripheral and LN LECs leads to congestion of lymphatics by myelomonocytic cells, with downstream impairment of lymphatic transport and consequently dampened antigen-specific immune responses (52). Similar roles for ACKR2 in orchestrating cell migration and resolving the inflammatory response have been described in a range of pathological contexts (50).…”

Section: Leukocyte Trafficking In Inflammation and Immunitysupporting

confidence: 55%

“…Atypical or decoy chemokine receptors have in a number of contexts been involved in modulating cancer progression through shaping the inflammatory response (7, 150). The atypical chemokine receptor ACKR2 has been shown to internalize and sequester an array of pro-inflammatory chemokines of the CC family (5, 49, 50). Mice deficient in ACKR2 had an increased susceptibility to the development of cutaneous tumors that was linked to the recruitment of immune cells (e.g., T cells and mast cells) to support their development (54).…”

Section: Cancermentioning

confidence: 99%

“…Interestingly other studies have shown that ACKR2-deficient mice develop enhanced symptoms of EAE (as well as collagen-induced arthritis) due to enhanced Th17 responses (161). These differences could be due to control of IL-17 production by ACKR2 (50).…”

Section: Other Pathologiesmentioning

confidence: 99%

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The Interplay Between Lymphatic Vessels and Chemokines

et al. 2019

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Chemokines are a family of small protein cytokines that act as chemoattractants to migrating cells, in particular those of the immune system. They are categorized functionally as either homeostatic, constitutively produced by tissues for basal levels of cell migration, or inflammatory, where they are generated in association with a pathological inflammatory response. While the extravasation of leukocytes via blood vessels is a key step in cells entering the tissues, the lymphatic vessels also serve as a conduit for cells that are recruited and localized through chemoattractant gradients. Furthermore, the growth and remodeling of lymphatic vessels in pathologies is influenced by chemokines and their receptors expressed by lymphatic endothelial cells (LECs) in and around the pathological tissue. In this review we summarize the diverse role played by specific chemokines and their receptors in shaping the interaction of lymphatic vessels, immune cells, and other pathological cell types in physiology and disease.

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Section: Leukocyte Trafficking In Inflammation and Immunitysupporting

confidence: 55%

Section: Cancermentioning

confidence: 99%

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The Interplay Between Lymphatic Vessels and Chemokines

et al. 2019

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“…ACKR2 is known as a chemokine decoy receptor that interacts with the majority of inflammatory CC chemokines, degrades them, and thus inhibits inflammation 114‐116 . ACKR2 is expressed in lymphatic tissues at high levels, particularly on lymphatic endothelial cells within noninflamed tissues 117,118 . The ACKR2 expression is induced by VEGF‐D, transforming growth factor‐β, IL‐6, interferon (IFN)‐α/β, and IFN‐γ 119 .…”

Section: Cxcl14 Candidate Receptorsmentioning

confidence: 99%

The multifarious roles of the chemokine CXCL14 in cancer progression and immune responses

Westrich

Vermeer

Colbert

et al. 2020

Molecular Carcinogenesis

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The chemokine CXCL14 is a highly conserved, homeostatic chemokine that is constitutively expressed in skin epithelia. Responsible for immune cell recruitment and maturation, as well as impacting epithelial cell motility, CXCL14 contributes to the establishment of immune surveillance within normal epithelial layers. Furthermore, CXCL14 is critical to upregulating major histocompatibility complex class I expression on tumor cells. Given these important roles, CXCL14 is often dysregulated in several types of carcinomas including cervical, colorectal, endometrial, and head and neck cancers. Its disruption has been shown to limit critical antitumor immune regulation and is correlated to poor patient prognosis.However, other studies have found that in certain cancers, namely pancreatic and some breast cancers, overexpression of stromal CXCL14 correlates with poor patient survival due to increased invasiveness. Contributing to the ambiguity CXCL14 plays in cancer is that the native CXCL14 receptor remains uncharacterized, although several candidate receptors have been proposed.Despite the complexity of CXCL14 functions, it remains clear that this chemokine is a key regulatory factor in cancer and represents a potential target for future cancer immunotherapies. K E Y W O R D Santitumor immunity, chemokine, CXCL14, HPV, immunotherapy

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“…7 By scavenging chemokines in tissue, ACKR2 plays important roles in limiting local inflammatory responses, in the resolution of inflammation, and in the regulation of adaptive immune responses. 7,8 ACKR2 is present in many parenchymal organs, including barrier tissues like the skin, gut, lung, and placenta, 9,10 with the major site of ACRK2 expression being on lymphatic endothelial cells. 11 Analysis of Ackr2-deficient mice demonstrated that ACKR2 limits inflammatory responses and tissue injury in several disease models, including skin inflammation, myocardial infarction, systemic infection with Mycobacterium tuberculosis, and toxic liver injury.…”

mentioning

confidence: 99%

The Atypical Chemokine Receptor 2 Limits Progressive Fibrosis after Acute Ischemic Kidney Injury

Lux

Blaut

Eltrich

et al. 2019

The American Journal of Pathology

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Following renal ischemia-reperfusion injury (IRI), resolution of inflammation allows tubular regeneration, whereas ongoing inflammatory injury mediated by infiltrating leukocytes leads to nephron loss and renal fibrosis, typical hallmarks of chronic kidney disease. Atypical chemokine receptor 2 (ACKR2) is a chemokine decoy receptor that binds and scavenges inflammatory CC chemokines and reduces local leukocyte accumulation. We hypothesized that ACKR2 limits leukocyte infiltration, inflammation, and fibrotic tissue remodeling after renal IRI, thus preventing progression to chronic kidney disease. Compared with wild type, Ackr2 deficiency increases CC chemokine ligand 2 levels in tumor necrosis factorestimulated tubulointerstitial tissue in vitro. In Ackr2-deficient mice with early IRI 1 or 5 days after transient renal pedicle clamping, tubular injury was similar to wild type, although accumulation of mononuclear phagocytes increased in postischemic Ackr2 À/À kidneys. Regarding long-term outcomes, Ackr2 À/À kidneys displayed more tubular injury 5 weeks after IRI, which was associated with persistently increased renal infiltrates of mononuclear phagocytes, T cells, Ly6C high inflammatory macrophages, and inflammation. Moreover, Ackr2 deficiency caused substantially aggravated renal fibrosis in Ackr2 À/À kidneys 5 weeks after IRI, shown by increased expression of matrix molecules, renal accumulation of a-smooth muscle actinepositive myofibroblasts, and bone marrowederived fibrocytes. ACKR2 is important in limiting persistent inflammation, tubular loss, and renal fibrosis after ischemic acute kidney injury and, thus, can prevent progression to chronic renal disease.

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ACKR2: An Atypical Chemokine Receptor Regulating Lymphatic Biology

Cited by 23 publications

References 55 publications

The Interplay Between Lymphatic Vessels and Chemokines

The Interplay Between Lymphatic Vessels and Chemokines

The multifarious roles of the chemokine CXCL14 in cancer progression and immune responses

The Atypical Chemokine Receptor 2 Limits Progressive Fibrosis after Acute Ischemic Kidney Injury

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