Helminth-derived peptide GK-1 induces Myd88-dependent pro-inflammatory signaling events in bone marrow-derived antigen-presenting cells

Montero, Laura; Cervantes‐Torres, Jacquelynne; Sciutto, Edda; Fragoso, Gladis

doi:10.1016/j.molimm.2020.09.015

Cited by 9 publications

(3 citation statements)

References 43 publications

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“…CD86 in antigen-presenting cells provides costimulatory signals to activate T cells through CD28 and CTLA4 binding [ 72 , 73 ]. Previous studies reported that CD86 was also up-regulated by helminth-derived peptide GK-1 in BMDM [ 74 ]. These changes in costimulatory and checkpoint proteins supports a potential immunoregulatory role of choline metabolism that may represent an underappreciated therapeutic potential in certain disease settings.…”

Section: Discussionmentioning

confidence: 99%

Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection

Ghorbani,

Kim,

Smith

et al. 2023

PLoS Pathog

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Type 2 cytokines like IL-4 are hallmarks of helminth infection and activate macrophages to limit immunopathology and mediate helminth clearance. In addition to cytokines, nutrients and metabolites critically influence macrophage polarization. Choline is an essential nutrient known to support normal macrophage responses to lipopolysaccharide; however, its function in macrophages polarized by type 2 cytokines is unknown. Using murine IL-4-polarized macrophages, targeted lipidomics revealed significantly elevated levels of phosphatidylcholine, with select changes to other choline-containing lipid species. These changes were supported by the coordinated upregulation of choline transport compared to naïve macrophages. Pharmacological inhibition of choline metabolism significantly suppressed several mitochondrial transcripts and dramatically inhibited select IL-4-responsive transcripts, most notably, Retnla. We further confirmed that blocking choline metabolism diminished IL-4-induced RELMα (encoded by Retnla) protein content and secretion and caused a dramatic reprogramming toward glycolytic metabolism. To better understand the physiological implications of these observations, naïve or mice infected with the intestinal helminth Heligmosomoides polygyrus were treated with the choline kinase α inhibitor, RSM-932A, to limit choline metabolism in vivo. Pharmacological inhibition of choline metabolism lowered RELMα expression across cell-types and tissues and led to the disappearance of peritoneal macrophages and B-1 lymphocytes and an influx of infiltrating monocytes. The impaired macrophage activation was associated with some loss in optimal immunity to H. polygyrus, with increased egg burden. Together, these data demonstrate that choline metabolism is required for macrophage RELMα induction, metabolic programming, and peritoneal immune homeostasis, which could have important implications in the context of other models of infection or cancer immunity.

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Section: Discussionmentioning

confidence: 99%

Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection

Ghorbani,

Kim,

Smith

et al. 2023

PLoS Pathog

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“…It is possible that the adaptive immune response against cysticerci is mediated by MHC, since different motifs were theoretically predicted in the GK-1 sequence [ 27 ]. On the other hand, GK-1 promotes the activation of NFκB in macrophages and dendritic cells through MyD88 [ 28 ], which in turn promote an inflammatory environment that result in an anti-tumoral response.…”

Section: Introductionmentioning

confidence: 99%

GK-1 effectively reduces angiogenesis and prevents T cell exhaustion in a breast cancer murine experimental model

Hernández-Aceves,

Cervantes-Torres,

Torres-García

et al. 2023

Cancer Immunol Immunother

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Breast cancer is the leading malignancy in women worldwide, both in terms of incidence and mortality. Triple-negative breast cancer (TNBC) is the type with the worst clinical outcomes and with fewer therapeutic options than other types of breast cancer. GK-1 is a peptide that in the experimental model of the metastatic 4T1 breast cancer has demonstrated anti-tumor and anti-metastatic properties. Herein, GK-1 (5 mg/kg, i.v.) weekly administrated not only decreases tumor growth and the number of lung macro-metastases but also lung and lymph nodes micro-metastases. Histological analysis reveals that GK-1 reduced 57% of the intra-tumor vascular areas, diminished the leukemoid reaction's progression, and the spleens' weight and length. A significant reduction in VEGF-C, SDF-1, angiopoietin-2, and endothelin-1 angiogenic factors was induced. Moreover, GK-1 prevents T cell exhaustion in the tumor-infiltrating lymphocytes (TILs) decreasing PD-1 expression. It also increased IFN-γ and granzyme-B expression and the cytotoxic activity of CD8+ TILs cells against tumor cells. All these features were found to be associated with a better antitumor response and prognosis. Altogether, these results reinforce the potential of GK-1 to improve the clinical outcome of triple-negative breast cancer immunotherapy. Translation research is ongoing towards its evaluation in humans.

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“…Interestingly, this cell line expresses KETc7, which is part of K7, a larger antigenic peptide whose properties had been characterized molecularly and immunologically ( Bobes et al., 2017 ). Furthermore, KETc7 contains an immunomodulatory epitope called GK-1 ( Montero et al., 2020 ), which has shown the highest protective capacity against murine cysticercosis ( Sciutto et al., 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Improvement of cell suspension cultures of transformed and untransformed Carica papaya cell lines, towards the development of an antiparasitic product against the gastrointestinal nematode Haemonchus contortus

Caltempa

Hernández

Pérez

et al. 2022

Front. Cell. Infect. Microbiol.

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Parasitic diseases have a major impact on human and animal health worldwide. Despite the availability of effective anti-parasitic drugs, their excessive and uncontrolled use has promoted the emergence of drug resistance, severely affecting ecosystems and human health. Thus, developing environmentally friendly antiparasitic treatments is urgently needed. Carica papaya has shown promising effects against infectious diseases. C. papaya embryogenic calluses were genetically modified by our research team to insert immunogenic peptides with the goal of developing an oral anti-cysticercosis vaccine. Among these callus cell lines, one labeled as CF-23, which expresses the KETc7 immunogenic peptide, induced the highest protection levels against experimental cysticercosis. In the process of designing a natural antiparasitic product based on C. papaya that simultaneously induced immunity against cysticercosis, both transformed (SF-23) and untransformed (SF-WT) suspension cultures were produced and optimized. Our results showed a better duplication time (td) for SF-23 (6.9 days) than SF-WT (13.02 days); thus, the SF-23 line was selected for scale-up in a 2-L airlift bioreactor, reaching a td of 4.4 days. This is the first time that a transgenic line of C. papaya has been grown in an airlift bioreactor, highlighting its potential for scale-up cultivation in this type of reactor. Considering the previously reported nematocidal activity of C. papaya tissues, their activity against the nematode Haemonchus contortus of aqueous extracts of SF-WT and SF-23 was explored in this study, with promising results. The information herein reported will allow us to continue the cultivation of the transgenic cell suspension line of C. papaya under reproducible conditions, to develop a new anti-parasitic product.

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Helminth-derived peptide GK-1 induces Myd88-dependent pro-inflammatory signaling events in bone marrow-derived antigen-presenting cells

Cited by 9 publications

References 43 publications

Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection

Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection

GK-1 effectively reduces angiogenesis and prevents T cell exhaustion in a breast cancer murine experimental model

Improvement of cell suspension cultures of transformed and untransformed Carica papaya cell lines, towards the development of an antiparasitic product against the gastrointestinal nematode Haemonchus contortus

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