Hypothalamic expression of the atypical chemokine receptor ACKR2 is involved in the systemic regulation of glucose tolerance

Fioravante, Milena; Bombassaro, Bruna; Ramalho, Albina F.; Moura, Rodrigo Ferreira de; Haddad-Tóvolli, Roberta; Solon, Carina; Dragano, Nathalia Romanelli Vicente; Vettorazzi, Jean Franciesco; Gaspar, Rodrigo S.; Ropelle, Eduardo R.; Carneiro, Everardo M.; Morari, Joseane; Velloso, Lı́cio A.

doi:10.1016/j.bbadis.2019.01.001

Cited by 10 publications

(6 citation statements)

References 27 publications

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“…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. Moreover, the novel role for ACKR2 in ductal epithelial branching required for the postnatal development of the mammary gland ( Wilson, et al 2017 , Wilson, et al 2020 ) is consistent with the prolactin signaling that is known to be essential for the branching phenotype of the mammary gland ( Slepicka et al 2021 ).…”

Section: Discussionsupporting

confidence: 79%

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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Section: Discussionsupporting

confidence: 79%

Phosphoproteomic mapping of CCR5 and ACKR2 signaling properties

Vacchini

Maffioli

Silvestre

et al. 2022

Front. Mol. Biosci.

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“…This diet-induced inflammatory response in the hypothalamus occurs in two phases. The first phase is characterized by increased production of chemokines (and chemokine-related proteins) such as C-X3-C motif chemokine ligand 1 (CX3CL1) also called as fractalkine, leukemia inhibitory factor (LIF), MCP-1, and atypical chemokine receptor 2 (ACKR2); and cytokines, such as TNF-α and IL-6, ranging from few hours to days after exposure to dietary lipids [40,47,117,118]. As the HFD is continued, the hypothalamic inflammatory response returns to near normal after 1 week, and then reappears as the second phase of inflammation, after 4 weeks [40,119].…”

Section: Metabolic Disorders Aging and Hypothalamic Inflammation A Obesity And Hypothalamic Inflammationmentioning

confidence: 99%

Hypothalamic inflammation in metabolic disorders and aging

Bhusal

Rahman

Suk

2021

Cell. Mol. Life Sci.

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The hypothalamus is a critical brain region for the regulation of energy homeostasis. Over the years, studies on energy metabolism primarily focused on the neuronal component of the hypothalamus. Studies have recently uncovered the vital role of glial cells as an additional player in energy balance regulation. However, their inflammatory activation under metabolic stress condition contributes to various metabolic diseases. The recruitment of monocytes and macrophages in the hypothalamus helps sustain such inflammation and worsens the disease state. Neurons were found to actively participate in hypothalamic inflammatory response by transmitting signals to the surrounding non-neuronal cells. This activation of different cell types in the hypothalamus leads to chronic, low-grade inflammation, impairing energy balance and contributing to defective feeding habits, thermogenesis, and insulin and leptin signaling, eventually leading to metabolic disorders (i.e., diabetes, obesity, and hypertension). The hypothalamus is also responsible for the causation of systemic aging under metabolic stress. A better understanding of the multiple factors contributing to hypothalamic inflammation, the role of the different hypothalamic cells, and their crosstalks may help identify new therapeutic targets. In this review, we focus on the role of glial cells in establishing a cause-effect relationship between hypothalamic inflammation and the development of metabolic diseases. We also cover the role of other cell types and discuss the possibilities and challenges of targeting hypothalamic inflammation as a valid therapeutic approach.

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“…Other evidence supporting diet-induced activation of the NF-κB pathway in the hippocampus comes from the decreased expression of IκBα, a negative regulator of NF-κB, in HFD-fed mice [150]. Accordingly, the atypical chemokine receptor 2 (ACKR2), a negative regulator of inflammation due to its scavenger activity for inflammatory chemokines, is differentially regulated in the hypothalamus of obese-prone and obese-resistant Swiss mice early after HFD exposure, with obese-prone mice showing a smaller increment in ACKR2 than obeseresistant mice, indicating impaired restriction of inflammation [184]. Another relevant pathway in diet-induced early inflammation is the fractalkine/CX3CR1 pathway.…”

Section: High-fat Diet-induced Metabolic Diseasementioning

confidence: 99%

Effects of diabetes on microglial physiology: a systematic review of in vitro, preclinical and clinical studies

Vargas-Soria

García-Alloza

Corraliza-Gomez

2023

J Neuroinflammation

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Diabetes mellitus is a heterogeneous chronic metabolic disorder characterized by the presence of hyperglycemia, commonly preceded by a prediabetic state. The excess of blood glucose can damage multiple organs, including the brain. In fact, cognitive decline and dementia are increasingly being recognized as important comorbidities of diabetes. Despite the largely consistent link between diabetes and dementia, the underlying causes of neurodegeneration in diabetic patients remain to be elucidated. A common factor for almost all neurological disorders is neuroinflammation, a complex inflammatory process in the central nervous system for the most part orchestrated by microglial cells, the main representatives of the immune system in the brain. In this context, our research question aimed to understand how diabetes affects brain and/or retinal microglia physiology. We conducted a systematic search in PubMed and Web of Science to identify research items addressing the effects of diabetes on microglial phenotypic modulation, including critical neuroinflammatory mediators and their pathways. The literature search yielded 1327 records, including 18 patents. Based on the title and abstracts, 830 papers were screened from which 250 primary research papers met the eligibility criteria (original research articles with patients or with a strict diabetes model without comorbidities, that included direct data about microglia in the brain or retina), and 17 additional research papers were included through forward and backward citations, resulting in a total of 267 primary research articles included in the scoping systematic review. We reviewed all primary publications investigating the effects of diabetes and/or its main pathophysiological traits on microglia, including in vitro studies, preclinical models of diabetes and clinical studies on diabetic patients. Although a strict classification of microglia remains elusive given their capacity to adapt to the environment and their morphological, ultrastructural and molecular dynamism, diabetes modulates microglial phenotypic states, triggering specific responses that include upregulation of activity markers (such as Iba1, CD11b, CD68, MHC-II and F4/80), morphological shift to amoeboid shape, secretion of a wide variety of cytokines and chemokines, metabolic reprogramming and generalized increase of oxidative stress. Pathways commonly activated by diabetes-related conditions include NF-κB, NLRP3 inflammasome, fractalkine/CX3CR1, MAPKs, AGEs/RAGE and Akt/mTOR. Altogether, the detailed portrait of complex interactions between diabetes and microglia physiology presented here can be regarded as an important starting point for future research focused on the microglia–metabolism interface.

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Hypothalamic expression of the atypical chemokine receptor ACKR2 is involved in the systemic regulation of glucose tolerance

Cited by 10 publications

References 27 publications

Phosphoproteomic mapping of CCR5 and ACKR2 signaling properties

Phosphoproteomic mapping of CCR5 and ACKR2 signaling properties

Hypothalamic inflammation in metabolic disorders and aging

Effects of diabetes on microglial physiology: a systematic review of in vitro, preclinical and clinical studies

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