Novel CMKLR1 Inhibitors for Application in Demyelinating Disease

Kumar, Vineet; LaJevic, Melissa; Pandrala, Mallesh; Jacobo, Sam A.; Malhotra, Sanjay V.; Zabel, Brian A.

doi:10.1038/s41598-019-43428-8

Cited by 12 publications

(9 citation statements)

References 32 publications

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“…Since that previous study, α-NETA has been employed to block the chemerin/CMKLR1 axis in CNS-related diseases, including preeclampsia [ 80 ] and neuroblastoma [ 81 ]. Moreover, α-NETA was reported to be well tolerated in mice [ 82 ]. According to our data, it barely affected the peripheral immune environment in our mouse preclinical GBM models, and α-NETA could precisely target both GBM cells and TAMs owing to the expression pattern of CMKLR1 in GBM tissue.…”

Section: Discussionmentioning

confidence: 99%

Chemerin enhances mesenchymal features of glioblastoma by establishing autocrine and paracrine networks in a CMKLR1-dependent manner

Shen

Liu

et al. 2022

Oncogene

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Glioblastoma multiforme (GBM) with mesenchymal features exhibits enhanced chemotherapeutic resistance and results in reduced overall survival. Recent studies have suggested that there is a positive correlation between the GBM mesenchymal status and immune cell infiltration. However, the mechanisms by which GBM acquires its mesenchymal features in a tumor immune microenvironment-dependent manner remains unknown. Here, we uncovered a chemerin-mediated autocrine and paracrine network by which the mesenchymal phenotype of GBM cells is strengthened. We identified chemerin as a prognostic secretory protein mediating the mesenchymal phenotype-promoting network between tumor-associated macrophages (TAMs) and tumor cells in GBM. Mechanistically, chemerin promoted the mesenchymal features of GBM by suppressing the ubiquitin-proteasomal degradation of CMKLR1, a chemerin receptor predominantly expressed on TAMs and partially expressed on GBM cells, thereby enhancing NF-κB pathway activation. Moreover, chemerin was found to be involved in the recruitment of TAMs in the GBM tumor microenvironment. We revealed that chemerin also enhances the mesenchymal phenotype-promoting ability of TAMs and promotes their M2 polarization via a CMKLR1/NF-κB axis, which further exacerbates the mesenchymal features of GBM. Blocking the chemerin/CMKLR1 axis with 2-(α-naphthoyl) ethyltrimethylammonium iodide disrupted the mesenchymal network and suppressed tumor growth in GBM. These results suggest the therapeutic potential of targeting the chemerin/CMKLR1 axis to block the mesenchymal network in GBM.

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Section: Discussionmentioning

confidence: 99%

Chemerin enhances mesenchymal features of glioblastoma by establishing autocrine and paracrine networks in a CMKLR1-dependent manner

Shen

Liu

et al. 2022

Oncogene

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“…The small molecule 2-( α naphtyl) ethyltrimethylammonium iodide (α-NETA) is a selective CMKLR1 antagonist, which suppresses autoimmune inflammatory response in the central nervous system ( Graham et al, 2014 ). Treatment with α-NETA and α-NETA analogues with structural modifications delay activation of autoimmune encephalomyelitis ( Graham et al, 2014 ; Kumar et al, 2019 ). Interestingly, α-NETA inhibits fat deposition in the liver and adipose tissue as well as lipid accumulation in the liver of high-fat fed mice and suppresses adipocyte gene expression in WAT demonstrating that α-NETA interferes with lipid metabolism ( Xue et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

The Chemerin-CMKLR1 Axis is Functionally important for Central Regulation of Energy Homeostasis

et al. 2022

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Chemerin is an adipokine involved in inflammation, adipogenesis, angiogenesis and energy metabolism, and has been hypothesized as a link between obesity and type II diabetes. In humans affected by obesity, chemerin gene expression in peripheral tissues and circulating levels are elevated. In mice, plasma levels of chemerin are upregulated by high-fat feeding and gain and loss of function studies show an association of chemerin with body weight, food intake and glucose homeostasis. Therefore, chemerin is an important blood-borne mediator that, amongst its other functions, controls appetite and body weight. Almost all studies of chemerin to date have focused on its release from adipose tissue and its effects on peripheral tissues with the central effects largely overlooked. To demonstrate a central role of chemerin, we manipulated chemerin signaling in the hypothalamus, a brain region associated with appetite regulation, using pharmacological and genetic manipulation approaches. Firstly, the selective chemerin receptor CMKLR1 antagonist α-NETA was administered i.c.v. to rats to test for an acute physiological effect. Secondly, we designed a short-hairpin-RNA (shRNA) lentivirus construct targeting expression of CMKLR1. This shRNA construct, or a control construct was injected bilaterally into the arcuate nucleus of male Sprague Dawley rats on high-fat diet (45%). After surgery, rats were maintained on high-fat diet for 2 weeks and then switched to chow diet for a further 2 weeks. We found a significant weight loss acutely and inhibition of weight gain chronically. This difference became apparent after diet switch in arcuate nucleus-CMKLR1 knockdown rats. This was not accompanied by a difference in blood glucose levels. Interestingly, appetite-regulating neuropeptides remained unaltered, however, we found a significant reduction of the inflammatory marker TNF-α suggesting reduced expression of CMKLR1 protects from high-fat diet induced neuroinflammation. In white and brown adipose tissue, mRNA expression of chemerin, its receptors and markers of adipogenesis, lipogenesis and brown adipocyte activation remained unchanged confirming that the effects are driven by the brain. Our behavioral analyses suggest that knockdown of CMKLR1 had an impact on object recognition. Our data demonstrate that CMKLR1 is functionally important for the central effects of chemerin on body weight regulation and neuroinflammation.

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“…15,52) Some studies suggested that Chemerin treatment inhibited the production of inflammatory cytokines and that this inhibitory effect mainly depended on CMKLR1. [52][53][54] Thus, pretreatment with suitable does of α-NETA, a novel small molecule antagonist of CMKLR1, 36,37) the anti-inflammatory effects of C9 were significantly blocked in Aβ 1-42 induced AD model mice. In BV2 cells, similar to the results of in vivo experiments, after pretreatment with α-NETA, C9 did not inhibit Aβ 1-42 induced inflammatory response.…”

Section: V) On Locomotor Behaviour In Micementioning

confidence: 98%

“…13) Figures 5 and 6 showed the anti-inflammatory effects of C9 in mice. According to Zabel and colleagues reports, 36,37) we synthesized and purified a novel CMKLR1 small molecule antagonist (α-NETA). The synthesis method, mass spectrometry and HPLC analysis of α-NETA are shown in Fig.…”

Section: Icv Administration Of C9 Improves the Object Recognition mentioning

confidence: 99%

Chemerin-9 Peptide Enhances Memory and Ameliorates Aβ<sub>1–42</sub>-Induced Object Memory Impairment in Mice

Lei

Xue

et al. 2020

Biological & Pharmaceutical Bulletin

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Accumulating evidence suggests that the inhibition of neuroinflammation is a potential target for therapeutic or preventive strategies for Alzheimer's disease (AD). Chemerin has attracted particular attention for its role in the regulation of inflammation. In addition, amyloid β 1-42 (Aβ 1-42) can interact with chemokine-like receptor 1 (CMKLR1), the receptor for chemerin, and induce microglial chemotaxis. Meanwhile, CMKLR1 is expressed in the brain, and both chemerin and Aβ 1-42 share the same receptor. Thus, we hypothesized that chemerin (C9), a chemerin-derived nonapeptide, may have the potential to ameliorate Aβ 1-42 mediated AD disease progression. The results showed that an intracerebroventricular (i.c.v.) injection of C9 (8 µg/kg) facilitated memory formation and improved memory retention, as evidenced by the results of both the novel object recognition test (NOR) and object location recognition (OLR) tasks. These memory-enhancing effects of C9 were also observed after C9 (2 µg/kg) was infused into the hippocampus. Moreover, we found that treatment with C9 reversed the deficits in memory and learning ability induced by oligomeric Aβ 1-42. Meanwhile, C9 also significantly inhibited Aβ 1-42-induced increases in the levels of pro-inflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the hippocampus. The same results were obtained for Western blotting and enzyme-linked immunosorbent assay (ELISA) experiments. Finally, we observed that C9 did not affect locomotor activity, suggesting that its improvement of memory is not a false positive induced by hypolocomotion. In conclusion, C9 may facilitate memory formation, prolong memory retention, and ameliorate Aβ 1-42-induced memory impairment, suggesting that C9 may potentially represent a novel strategy for the treatment of AD.

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Novel CMKLR1 Inhibitors for Application in Demyelinating Disease

Cited by 12 publications

References 32 publications

Chemerin enhances mesenchymal features of glioblastoma by establishing autocrine and paracrine networks in a CMKLR1-dependent manner

Chemerin enhances mesenchymal features of glioblastoma by establishing autocrine and paracrine networks in a CMKLR1-dependent manner

The Chemerin-CMKLR1 Axis is Functionally important for Central Regulation of Energy Homeostasis

Chemerin-9 Peptide Enhances Memory and Ameliorates Aβ<sub>1–42</sub>-Induced Object Memory Impairment in Mice

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