Cell stem cell, Journal Year: 2024, Volume and Issue: 31(11), P. 1591 - 1611.e8
Published: Oct. 14, 2024
Language: Английский
Immunity, Journal Year: 2024, Volume and Issue: 57(11), P. 2669 - 2687.e6
Published: Oct. 11, 2024
Language: Английский
Citations
6
Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14
Published: Aug. 12, 2024
Ferroptosis is an iron-dependent form of cell death that results from excess lipid peroxidation in cellular membranes. Within the last decade, physiological and pathological roles for ferroptosis have been uncovered autoimmune diseases, inflammatory conditions, infection, cancer biology. Excitingly, metabolism may be targeted to induce by cancers are resistant other forms death. sensitivity regulated oxidative stress, metabolism, iron which all influenced tumor microenvironment (TME). Whereas some types shown adapt these stressors, it not clear how immune cells regulate their sensitivities ferroptosis. In this review, we discuss mechanisms different subsets, influences infiltrate TME, interactions can determine epithelial-to-mesenchymal transition (EMT) metastasis. While much focus has placed on inducing cells, important considerations ferroptosis-modulating strategies impact anti-tumor immunity. From perspective, also promising immunotherapies field challenges associated with targeting specific populations.
Language: Английский
Citations
5
International Journal of Cancer, Journal Year: 2022, Volume and Issue: 151(12), P. 2265 - 2277
Published: Sept. 2, 2022
The immunosuppressive tumor microenvironment (TME) in glioblastoma (GBM) is mainly driven by tumor-associated macrophages (TAMs). We explored whether their sustained iron metabolism and activity were correlated, blocking the central enzyme of heme catabolism pathway, oxygenase-1 (HO-1), could reverse tolerogenic activity. To this end, we investigated bone marrow-derived (BMDMs) isolated from GBM specimens vitro-derived (Mφ) healthy donor (HD) blood monocytes. found that HO-1 inhibition abrogated both BMDMs Mφ, immunosuppression requires cell-to-cell contact soluble factors, as abolished IL-10 release, significantly reduced STAT3 activation well PD-L1 expression. Interestingly, not only did downregulate IDO1 ARG-2 gene expression, but also enzymatic Moreover, T cell status affected expression activity, which upregulated presence activated, resting, cells. Our results highlight crucial role TME demonstrate feasibility reprogramming them an alternative therapeutic strategy for restoring immune surveillance.
Language: Английский
Citations
22
Trends in Molecular Medicine, Journal Year: 2022, Volume and Issue: 28(11), P. 906 - 915
Published: Sept. 10, 2022
Macrophages are the central hub for detoxification of oxidative hemoglobin and heme. This protective function progresses either via engulfment controlled degradation red blood cells (RBCs) or receptor-mediated clearance RBC toxins.Intracellular heme signaling BACH1, SPI-C, NRF2, ATF1 orchestrates macrophage transformation into specialized erythrophagocytes with optimized antioxidant iron recycling capacity.Novel discoveries demonstrated that have a unique anti-inflammatory phenotype disease- context-dependent modulator effect on host defense, wound healing, atherosclerosis, cancer progression.Enhancement targeted suppression erythrophagocyte functions may be exploited as novel therapeutic strategies. Hemolysis is ubiquitous pathology defined premature cell destruction within circulation local tissues. One most archetypal macrophages phagocytosis damaged extravasated cells, preventing extracellular release toxic Upon erythrophagocytosis, spiking intracellular concentrations drive erythrophagocytes, leveraging antioxidative capacities to defend against hemolytic stress. coordinated by regulatory network comprising transcription factors ATF1. Erythrophagocytes negatively regulate inflammation immunity modulate disease-specific outcomes in anemia, cancer. In this opinion article, we outline known presumed their implications innovation research. The term hemolysis describes dysfunction breakdown [1.Kaushansky K. et al.Williams Hematology. McGraw-Hill Education, 2016Google Scholar]. blood, results from excessive altered RBCs liver spleen rupture membrane-dysfunctional circulation. Hemolytic anemias caused broad range genetic acquired (see Clinician's corner). From broader perspective, pathophysiological concept its downstream consequences should not restricted anemias, it also occurs ubiquitously secondary extravasation tissues [2.Vallelian F. al.Hemolysis, free toxicity scavenger protein therapeutics.Blood. 2022; (Published online June 3, 2022)https://doi.org/10.1182/blood.2022015596Crossref PubMed Scopus (4) Google Examples pathological numerous at macroscopic microscopic scales, including tissue trauma, spontaneous bleeding, such subarachnoid hemorrhage, containing immature leaky vessels, tumors large atherosclerotic plaques. these conditions, membranes become dysfunctional closed compartments exposed cell-free (Hb) space, Hb toxins due uncontrolled biochemical reactivity endogenous oxidants (Box 1 Figure 1) [3.Schaer D.J. al.Hemolysis revisited: exploring hemin scavengers class proteins.Blood. 2013; 121: 1276-1284Crossref (462) Scholar,4.Gladwin M.T. an intrinsic mechanism human disease.J. Clin. Invest. 2012; 122: 1205-1208Crossref (106) Physiological protection conferred evolutionary conserved hierarchically organized system proteins haptoglobin hemopexin, which strong capacity neutralize adverse effects heme, respectively Scholar,5.Buehler P.W. al.Haptoglobin therapeutics compartmentalization toxicity.Trends Mol. Med. 2020; 26: 683-697Abstract Full Text PDF (32) Scholar,6.Schaer al.Haptoglobin, related defense pathways-basic science, clinical perspectives, drug development.Front. Physiol. 2014; 5: 415Crossref (183) Scholar].Box 1Systemic localized stressor homeostasisRed contain oxygen carrier non-amino acid component exceeding 15 mM. high concentration distinct environment supports structural functional dynamics tetramer, can bind through demand- supply-regulated lung metabolically active protects cardiovascular microenvironments toxicity. highly reactive molecules. vasodilator nitric oxide, other oxidants, unsaturated lipids defines when present outside RBCs. main vasoconstriction leading cardiopulmonary ischemia, oxidation-driven injury, heme-ligation Toll-like receptors (TLRs) trigger Scholar] text). Additional heme-excess been associated heme-binding cellular proteasome [77.Vallelian al.Proteasome inhibition reactions disrupt homeostasis during stress.Cell Death Differ. 2015; 22: 597-611Crossref (37) cytoskeleton [78.Martins R. al.Heme drives hemolysis-induced susceptibility infection disruption phagocyte functions.Nat. Immunol. 2016; 17: 1361-1372Crossref (94) Red With clear toxin release. last few years, heme-driven pathways endorsing metabolic immune-functional phenotype: Glossary). Erythrophagocyte enables adaptation systemic Their primary detoxifying process, regulating immunity, translating environmental stimuli regenerative impetus. It now emerging depending disease context intensity, duration, site hemolysis, attenuation or, occasionally, acceleration. summarize research framework disease-modifying conditions. As first line recognize engulf but still intact shuttle contents [7.Theurl I. al.On-demand erythrocyte disposal requires transient liver.Nat. 945-951Crossref (230) Scholar,8.Knutson M. Wessling-Resnick Iron metabolism reticuloendothelial system.Crit. Rev. Biochem. Biol. 2003; 38: 61-88Crossref (254) play essential roles clearing complexes composed hemopexin. internalize specifically endocytosis CD163 [9.Kristiansen al.Identification haemoglobin receptor.Nature. 2001; 409: 198-201Crossref (1278) Scholar, 10.Schaer al.CD163 receptor native chemically modified hemoglobins absence haptoglobin.Blood. 2006; 107: 373-380Crossref (226) 11.Schaer C.A. al.Constitutive mediates hemoglobin-heme uptake determines noninflammatory transcriptional response hemoglobin.Circ. Res. 99: 943-950Crossref (212) CD91 [12.Hvidberg V. scavenging hemopexin-heme complexes.Blood. 2005; 106: 2572-2579Crossref (331) (Figure 1). Free low affinity albumin [13.Kuzelova al.Kinetics interaction proteins: aggregation state.Biochim. Biophys. Acta. 1997; 1336: 497-501Crossref (56) Scholar,14.Fasano al.The extraordinary ligand binding properties serum albumin.IUBMB Life. 57: 787-796Crossref (794) Scholar], internalization heme–albumin has used experimentally induce heme-directed polarization culture [15.Vallelian al.Revisiting putative role inflammation.Pharmacol. Perspect. 2018; 6e00392Crossref (34) Following lysosomal degradation, exported cytosol specific transporters [primarily transporter HRG1/solute family 48 member (SLC48A1)] [16.White C. al.HRG1 transport phagolysosome erythrophagocytosis.Cell Metab. 261-270Abstract (145) catabolized oxygenase (HMOX-1) [11.Schaer Scholar,17.Poss K.D. Tonegawa S. Heme required mammalian reutilization.Proc. Natl. Acad. Sci. U. A. 94: 10919-10924Crossref (859) Scholar,18.Tenhunen enzymatic conversion bilirubin microsomal oxygenase.Proc. 1968; 61: 748-755Crossref (1504) exhibit remarkable plasticity, enabling them rapidly adapt stressors milieu. When becomes imbalanced inflammatory circulate eliminate pathogens, infected well coordinate [19.Sica Mantovani Macrophage plasticity polarization: vivo veritas.J. 787-795Crossref (3809) Towards end spectrum, maintain integrity repairing injured tissue, senescent resolving [20.Gordon Martinez F.O. Alternative activation macrophages: functions.Immunity. 2010; 32: 593-604Abstract (2760) classical bipolar denoted IFN-gamma-induced M1 IL-4-induced anti-inflammatory, M2 [21.Locati al.Diversity, mechanisms, significance plasticity.Annu. Pathol. 15: 123-147Crossref (404) However, phenotypes much more heterogeneous vivo, displaying determined developmental origin, residence, disease-propagated signals Scholar,21.Locati 22.Italiani P. Boraschi D. monocytes M1/M2 phenotypical vs. differentiation.Front. 514Crossref (1069) 23.Gordon al.Macrophage heterogeneity tissues: phenotypic diversity functions.Immunol. 262: 36-55Crossref (442) 24.Murray P.J. Wynn T.A. Protective pathogenic subsets.Nat. 2011; 11: 723-737Crossref (3253) Systemic provides signal transforming adaptive phenotype, promoting coordinating regeneration healing [25.Boyle J.J. al.Coronary intraplaque hemorrhage evokes atheroprotective phenotype.Am. J. 2009; 174: 1097-1108Abstract (237) 26.Kaempfer T. al.Extracellular polarizes proteome toward Hb-clearance, enhanced suppressed HLA 2 expression.J. Proteome 10: 2397-2408Crossref (33) 27.Vallelian al.Glucocorticoid treatment skews monocyte differentiation hemoglobin-clearance heme-iron capacity.Blood. 116: 5347-5356Crossref (66) pathway underlying driven surge following heme–protein Scholar,25.Boyle Scholar,28.Pfefferlé transforms erythrophagocytes.J. 130: 5576-5590Crossref (20) multiple independent observations across models hemorrhages wounds, plaques, cancer, researchers observed heme-induced iron-recycling attenuated immune functions. These macrophages, later called had gene expression profile clearly deviated spectrum IFN-gamma (M1) IL-4 (M2) induced ways [28.Pfefferlé Different reported progression along various factor networks, ATF1, ultimately converging very similar characteristics. one unresolved questions field determine mechanisms erythrophagocytosis activate cascades tissue–environmental Outstanding questions). sections, will discuss how attenuate exacerbate processes tissue- type-specific context. To provide systematic approach, classify heme-polarized compartment tissue-localized lesions, tumor microenvironment. cleared liver. Under homeostatic turnover pulp (RPMs) subpopulation splenic phagocytes phagocytosing [29.Mebius R.E. Kraal G. Structure spleen.Nat. 606-616Crossref (1426) 30.Klei T.R.L. al.From cradle grave: erythropoiesis erythrophagocytosis.Front. 2017; 8: 73Crossref (120) 31.Korolnek Hamza trafficking birth death cells.Blood. 125: 2893-2897Crossref (118) 32.Klei turnover.Blood. 136: 1579-1589PubMed constituent, Hb, digested phagolysosomes, then HRG1/SLC48A1 Scholar,33.Rajagopal al.Haem regulated concerted HRG-1 proteins.Nature. 2008; 453: 1127-1131Crossref (221) Intracellular RPM identity deactivating repressor controls genes, HMOX-1 SPI-C [34.Sun al.Hemoprotein Bach1 regulates enhancer availability oxygenase-1 gene.EMBO 2002; 21: 5216-5224Crossref (512) Scholar,35.Ogawa derepression Maf recognition element direct Bach1.EMBO 20: 2835-2843Crossref (415) Activation directs peripheral RPMs; SPI-C-deleted mice deficient RPMs [36.Haldar al.Heme-mediated induction promotes macrophages.Cell. 156: 1223-1234Abstract (270) 37.Kohyama al.Role Spi-C development homeostasis.Nature. 457: 318-321Crossref (304) 38.Alam M.Z. connection: linking erythrocytes biology.Front. 33Crossref 2, panel). enzyme converts iron, carbon monoxide, biliverdin. Carbon monoxide act molecule biliverdin further reduced [17.Poss Depending demand, stored intracellularly ferritin–iron complex plasma transferrin, shuttles bone marrow erythropoietic recycling. Collectively, support physiological blue erythrolysis over anemia corner), resident recruited acquire erythrophagocytic function. transformation, pool largest contributor overall greatly On-demand recruitment under control Csf-1 important avoiding intravascular lysis membrane-altered Single-cell RNA sequencing analysis mouse model spherocytosis details model, display genes involved storage export pathways. Moreover, importantly, show major histocompatibility II (MHC II), resistance (TLR) agonists, interferon, CD40 ligation, impaired bacterial killing Scholar,39.Olonisakin T.F. al.Stressed induces immunosuppression sepsis heme-mediated STAT1 dysregulation.J. 131e137468Google Scholar,40.Pfefferlé al.Acute suppress anti-CD40 antibody-induced necro-inflammatory disease.Front. 2021; 12680855Crossref (3) mainly single factor, NRF2 (encoded Nfe2I2), activated deactivation cytoplasmic NRF2-binding KEAP1 principal activator oxidant stress was recently identified inflammation-related [41.Taguchi al.Molecular Keap1–Nrf2 evolution.Genes Cells. 16: 123-140Crossref (1059) Scholar,42.Kobayashi E.H. al.Nrf2 suppresses blocking proinflammatory cytokine transcription.Nat. Commun. 7: 11624Crossref (869) Therefore, heme-signaling sufficiently explains key characteristics (i.e., functions). inactivation HMOX-1, post-transcriptional regulation elements (e.g., ferritin transferrin receptor) Scholar,43.Rouault disease.Nat. Chem. 2: 406-414Crossref (780) Besides imprint liver, exposure exert profound hematopoietic trajectories. Myeloid progenitors source monocyte-derived granulocytes, certain dendritic [44.Geissmann al.Development monocytes, cells.Science. 327: 656-661Crossref (2147) experiments using progenitors, heme-enforced generation on-demand occurred expense myeloid-derived [45.Vallelian al.Heme-stress fate trajectories towards pulp-like anemia.Cell 29: 1450-1465Crossref sickle spherocytosis, led deficiency spleen, accompanied antigen presentation CD4 T priming represent aspect hyposplenism, immunodeficiency patients particularly [46.Kato G.J. al.Sickle Dis. Primers. 4: 18010Crossref (256) Schol
Language: Английский
Citations
20
Cell stem cell, Journal Year: 2024, Volume and Issue: 31(11), P. 1591 - 1611.e8
Published: Oct. 14, 2024
Language: Английский
Citations
4