Establishing Tyro3, Axl, and Mertk Chinese hamster ovary (CHO) reporter cell lines for cancer immunology and therapeutic applications

Methods in cell biology, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Language: Английский

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Phagocytic clearance of dying cells and its implications

Immunological Reviews, Journal Year: 2023, Volume and Issue: 319(1), P. 4 - 6

Published: Oct. 1, 2023

It is estimated that an average adult human turns over roughly 330 ± 20 billion cells every day as part of healthy living.1, 2 This translates to 0.4% our body mass. Such a large number for cell turnover then begs the question—what are these and why? The reasons this multi-factorial. First, there in have finite life span, such neutrophils (~1 day) erythrocytes (~120 days), also other types many hematopoietic span few days weeks; need be removed after their useful replaced by new cells. Second, aspects development where we generate excess cells, which only deemed fit progress full maturation, rest undergo death removed; examples include T thymus, B bone marrow, neurogenesis brain.1 Third, “damaged” emerge daily body, due light/UV damage, example skin photoreceptors eye.3 Thus, all events result undergoing essentially organs tissues, albeit at different magnitude.2 Although forms processes, destined die via homeostatic do so primarily process caspase-dependent apoptosis.4 What happens dying cells? Despite billions per day, when one looks it hard recognize even those with high cellular turnover. because recognition clearance remarkably efficient.5, 6 Just like dedicated set molecules mechanisms induce programmed death, possess machinery remove cells.7 under homeostasis conditions occurs quickly, efficiently, from immunological perspective, quietly.8 worth noting just apoptotic machinery, processes highly conserved evolutionarily, studies nematode, flies, zebrafish, mice, humans established components process.9, 10 volume Immunological Reviews focuses on its implications disease. While phagocytosis, phagocytes has been termed “efferocytosis,” term originally coined Dr. Peter Henson. (where “effero” means “carry grave”).11 should distinguished Fc receptor mediated phagocytosis or complement receptor-mediated involves opsonization target specific ligands uptake respective receptors. A key distinction does not immune response; further efferocytosis actively anti-inflammatory.8 makes sense considers fact if were inflammatory response clear may end up walking bags inflammation. However, failure promptly can secondary necrosis lead sequelae, detailed some chapters volume. Works laboratories now steps removal cells.1, 12 first step When macrophages, dendritic neighbors close proximity cell, recognized receptors engulfing leading subsequent intracellular signaling, cytoskeletal reorganization, corpse internalization.13 exposed apoptosis, best exposure phospholipid phosphatidylserine (PtdSer).14, 15 PtdSer normally kept active energy dependent inner leaflet but gets outer process.15, 16 turn, multiple receptors—either directly, indirectly, intermediary bridging molecules.16, 17 As chapter, Tal Brustyn-Cohen details described families linked namely TAM receptors.18 These indirectly Gas6 Protein S bind PtdSer, chapter role contexts highlights physiology. One challenges studying mammals homologues engulfment signaling molecules, complexities arise individual knockouts often phenotype. defining function well visualizing vivo challenge past couple decades. Will Wood, Andrew Davidson, colleagues detail beautiful model systems fruit fly Drosophila provided insights.19 They approaches developed visualize apoptosis vivo, plus molecular employed macrophages After phagocyte engulfs second ensues—that is, digesting corpse. no small feat, another nearly same size itself. Further, engulf cells.20 Mylvaganam Freeman take comprehensive approach how resolves phagolysosome membrane traffic, solute carriers managing contents put disease lysosomal storage disorders.21 Another inherent faces handle biomass. To way, basically doubles lipids, carbohydrates, proteins, name contents. ingest corpses succession, greater dealing metabolic overload.20, 22 Shilperoort, Tabas, beautifully macrophage immunometabolism.23 amino acids arginine methionine conversion within impact continued additional corpses, responses, processes. authors lactate regulation relevance atherosclerosis, limitations current studies. get lot attention “professional phagocytes” capable nonprofessional phagocytes. slower kinetics than they play important routine body. retinal pigmented epithelial (RPE) retina provide example, basis “used” damaged light during allow place.24, 25 aspect RPE postmitotic, born RPE. throughout lifetime, addition nurse functions maintain retina. Silvia Finnemann background receptors, RPE-mediated clearance, diseases disturbed inflammation.26 fully appreciate importance garbage workers until go strike, “cellular crew” gotten much better appreciation two decades failures associated contribute links cancer.8 four final Christopher Gregory complexity cancer context.27 He products (including extracellular vesicles factors released cells) regulate tumor microenvironment; includes responses solid tumors, either direct contact products, reshaping microenvironment growth. followed description Wagoner, Michael Elliott, antibody-mediated cells—which antibody-bound macrophages.28 present modifications FcR-mediated overcome them. become increasingly auto-inflammatory arthritis, certain colitis component defective minimally release late stage promote pro-inflammatory milieu, chronic inflammation.1 self-antigens presented environment, evolve autoimmunity. Schneider Arandjelovic arthritis. Interestingly, roles, neutrophil migration arthritic joints turn arthritis.29 Lastly, Gabrielle Fredman Sayeed Khan discuss specialized pro-resolving mediators (SPMs) dead cells.30 highlight SPMs facilitating necroptotic link non-resolving atherosclerosis. In sum, investigations die, removed, consequences regulated efficient exploded. led remarkable increase knowledge mechanisms, defects states tissue contexts. collection reviews, contributions own laboratories, discoveries larger context what known, challenges, about addressing next questions field. research turnover, single tissue, bound continue, modulating providing opportunities treating diseases.31 work was supported grants K.S.R. NIAID (R01AI159551), NHLBI (P01HL120840), BJC Investigator funds Washington University School Medicine (St. Louis, MO). author declares competing interests. Data sharing applicable article data created analyzed study.

Language: Английский

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Bcl-2 inhibition in the treatment of hematologic malignancies

Frontiers in Hematology, Journal Year: 2023, Volume and Issue: 2

Published: Dec. 4, 2023

Apoptosis is a tightly regulated process of cell death occurring through extrinsic and intrinsic pathways. The Bcl-2 family proteins implicated in the pathway encompasses both pro-apoptotic anti-apoptotic proteins. Anti-apoptotic are frequently overexpressed hematologic malignancies so inhibitors have been developed to combat these malignancies. first so-far only FDA-approved inhibitor has venetoclax, initially for treatment chronic lymphocytic leukemia (CLL) with 17-p deletion as second-line agent, followed by later expansion all CLL selected acute myeloid (AML) indications. Venetoclax other members demonstrated significant potential. However, their use requires careful consideration disease indication, along biomarkers associated optimal drug combinations. Side-effect profiles specific patterns resistance must be considered well. In this review, we examine detail characteristics role apoptosis. We discuss development that led first-in-class approval relevant considerations. Finally, future directions domain pharmaceutical development.

Language: Английский

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