Abstract Mitochondrial dysfunction can elicit multiple inflammatory pathways, especially when apoptotic caspases are inhibited. Such an inflammatory program is negatively regulated by the autophagic ...disposal of permeabilized mitochondria. Recent data demonstrate that the ubiquitination of mitochondrial proteins is essential for NEMO-driven NF-kB activation downstream of mitochondrial permeabilization.
Cellular and organismal aging have been consistently associated with mitochondrial dysfunction and inflammation. Accumulating evidence indicates that aging-related inflammatory responses are ...mechanistically linked to compromised mitochondrial integrity coupled with mtDNA-driven CGAS activation, a process that is tonically inhibited by mitophagy.Cellular and organismal aging have been consistently associated with mitochondrial dysfunction and inflammation. Accumulating evidence indicates that aging-related inflammatory responses are mechanistically linked to compromised mitochondrial integrity coupled with mtDNA-driven CGAS activation, a process that is tonically inhibited by mitophagy.
Atherosclerosis is a chronic inflammatory disease driven by hypercholesterolemia. During aging, T cells accumulate cholesterol, potentially affecting inflammation. However, the effect of cholesterol ...efflux pathways mediated by ATP-binding cassette A1 and G1 (ABCA1/ABCG1) on T cell-dependent age-related inflammation and atherosclerosis remains poorly understood. In this study, we generate mice with T cell-specific Abca1/Abcg1-deficiency on the low-density-lipoprotein-receptor deficient (Ldlr
) background. T cell Abca1/Abcg1-deficiency decreases blood, lymph node, and splenic T cells, and increases T cell activation and apoptosis. T cell Abca1/Abcg1-deficiency induces a premature T cell aging phenotype in middle-aged (12-13 months) Ldlr
mice, reflected by upregulation of senescence markers. Despite T cell senescence and enhanced T cell activation, T cell Abca1/Abcg1-deficiency decreases atherosclerosis and aortic inflammation in middle-aged Ldlr
mice, accompanied by decreased T cells in atherosclerotic plaques. We attribute these effects to T cell apoptosis downstream of T cell activation, compromising T cell functionality. Collectively, we show that T cell cholesterol efflux pathways suppress T cell apoptosis and senescence, and induce atherosclerosis in middle-aged Ldlr
mice.
Defective cholesterol efflux pathways in mice promote the expansion of hematopoietic stem and progenitor cells and a bias toward the myeloid lineage, as observed in chronic myelomonocytic leukemia ...(CMML). Here, we identify 5 somatic missense mutations in ABCA1 in 26 patients with CMML. These mutations confer a proliferative advantage to monocytic leukemia cell lines in vitro. In vivo inactivation of ABCA1 or expression of ABCA1 mutants in hematopoietic cells in the setting of Tet2 loss demonstrates a myelosuppressive function of ABCA1. Mechanistically, ABCA1 mutations impair the tumor-suppressor functions of WT ABCA1 in myeloproliferative neoplasms by increasing the IL-3Rβ signaling via MAPK and JAK2 and subsequent metabolic reprogramming. Overexpression of a human apolipoprotein A-1 transgene dampens myeloproliferation. These findings identify somatic mutations in ABCA1 that subvert its anti-proliferative and cholesterol efflux functions and permit the progression of myeloid neoplasms. Therapeutic increases in HDL bypass these defects and restore normal hematopoiesis.
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•ABCA1 somatic mutations were identified in CMML patients•ABCA1 mutations fail to repress myeloproliferative neoplasms in Tet2-deficient mice•ABCA1 mutations sustain IL-3Rβ signaling-driven myelopoiesis in Tet2-deficient HSPCs•Overexpression of apoA-1 overcomes ABCA1/TET2 co-mutant myeloproliferative neoplasms
Viaud et al. show that ABCA1 mutants identified in CMML patients diminish the tumor-suppressor functions of ABCA1 and cooperate with Tet2 loss to confer the hypersensitivity of myeloid progenitors to IL-3 receptor β canonical signaling, which can be prevented by raising HDL levels.
BackgroundPT-112 is a novel immunogenic small molecule1 under Phase II clinical development for cancer therapy.2–8 Besides mediating cytostatic and cytotoxic effects in numerous human and mouse ...cancer cells, PT-112 elicits various danger signals that are linked to immunogenic cell death (ICD) such as calreticulin exposure, as well as ATP and HMGB1 secretion.1 9–11 Accordingly, mouse cancer cells succumbing to PT-112 in vitro efficiently protect immunocompetent, tumor-naïve mice from challenge with living cancer cells of the same type.1 9 Moreover, PT-112 synergizes with PD-1 or PD-L1 blockade to control mouse tumors developing in immunologically competent hosts.1 9 This work focuses on elucidating the underlying mechanisms of PT-112-induced ICD.MethodsWe harnessed a panel of human and mouse cell lines optionally engineered to lack specific genes involved in mitochondrial apoptosis (namely, Bcl2, Bax and Bak1) coupled with flow cytometry, immunoblotting, RT-PCR, immunofluorescence microscopy and clonogenic assays to determine the impact of reticular and mitochondrial events on the established ability of PT-112 to kill malignant cells in an immunogenic manner.1ResultsIn line with previous findings,10–13 PT-112 elicited eukaryotic translation initiation factor 2 subunit alpha (EIF2S1, best known as eIF2α) phosphorylation and mitochondrial dysfunction in malignant cells, a process that was accompanied by the release of interferogenic mitochondrial DNA (mtDNA)14 in the cytoplasm of PT-112 treated cells, and was differentially affected by the deletion of Bcl2, Bax, Bak1, or Bax plus Bak1. Similarly, the lack of Bcl2, Bax, Bak1, or Bax plus Bak1 had a differential impact on the ability of PT-112 to elicit early signs of mitochondrial apoptosis including reactive oxygen species (ROS) generation, mitochondrial transmembrane potential loss and ultimately plasma membrane permeabilization.ConclusionsER stress and mitochondrial dysfunction appear to underlie the ability of PT-112 to drive ICD, the integrated stress response, and viral mimicry. This is in line with the well-established connections between ER stress and cytoplasmic nucleic acid sensing, which are pristine mechanisms of antiviral defense in mammalian cells, with the capacity of dying cells to emit immunostimulatory signals.15 Whether PT-112-driven stress also shifts the antigenic properties of cancer cells as a consequence of the accumulation of non-mutational neoantigens16 remains to be determined. Despite these and other open questions, PT-112 stands out as a powerful immunotherapeutic agent with promising clinical activity in patients with a variety of tumors1 under Phase II clinical development for cancer therapy.2–8ReferencesYamazaki T, et al. PT-112 induces immunogenic cell death and synergizes with immune checkpoint blockers in mouse tumor models. Oncoimmunology. 2020;9(1):1721810Karp DD, et al. Phase I study of PT-112, a novel pyrophosphate-platinum immunogenic cell death inducer, in advanced solid tumours. EClinicalMedicine. 2022;49:101430.Bryce AH, et al. A phase 1b study of novel immunogenic cell death inducer PT-112 plus PD-L1 inhibitor avelumab in metastatic castrate-resistant prostate cancer (mCRPC) patients. Journal of Clinical Oncology. 2021;39(15_suppl):e17025-e17025. doi:10.1200/JCO.2021.39.15_suppl.e17025Kourelis T, et al. A Phase I Dose Escalation Study of PT-112 in Patients with Relapsed or Refractory Multiple Myeloma. Blood. 2020;136(Supplement 1):9–10.Karp DD, et al. Phase Ib dose escalation study of novel immunogenic cell death (ICD) inducer PT-112 plus PD-L1 inhibitor avelumab in solid tumours. Annals of Oncology. 2020;31:S708.Imbimbo M, et al. A phase IIa study of the novel immunogenic cell death (ICD) inducer PT-112 plus avelumab (‘PAVE’) in advanced non-small cell lung cancer (NSCLC) patients (pts). Immuno-Oncology and Technology. 2022;16:100237.Swift S, et al. Preliminary efficacy, safety, and immunomodulatory effects of PT-112 from a phase 2 proof of concept study in patients (pts) with thymic epithelial tumors (TETs). Journal of Clinical Oncology. 2023;41(16_suppl):e20647-e20647.Bryce AH, et al. A phase 2 study of immunogenic cell death inducer PT-112 in patients with metastatic castration-resistant prostate cancer. Journal of Clinical Oncology. 2023;41(6_suppl):TPS292-TPS292.Yamazaki T, Ames TD, Galluzzi L, Potent induction of immunogenic cell death by PT-112. Cancer Immunology Research. 2019;7(2_Supplement):B199-B199.Soler-Agesta R, et al. PT-112 induces potent mitochondrial stress and immunogenic cell death in human prostate cancer cell lines. Cancer Research. 2022;82(12_Supplement):1115–1115.Soler-Agesta R, et al. PT-112 Induces Mitochondrial Stress and Immunogenic Cell Death, Targeting Tumor Cells with Mitochondrial Deficiencies. Cancers (Basel). 2022;14(16):3851.Soler-Agesta R, et al. Characterization of differential metabolic phenotypes and PT-112-induced mitochondrial effects in human prostate cancer cells. European Journal of Cancer. 2022;174(Supplement 1):S39.Yamazaki T, et al. Immunologically relevant effects of PT-112 on cancer cell mitochondria. Journal for ImmunoTherapy of Cancer. 2022;10(Suppl 2):A1162-A1162.Yamazaki T, et al. Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy. Nature Immunology. 2020;21(10):1160–1171.Kroemer G, et al. Immunogenic cell stress and death. Nature Immunology. 2022;23(4):487–500.Stern LJ, et al. Non-mutational neoantigens in disease. Nat Immunol. 2023; IN PRESS.
Macrophages are tissue-resident cells that act as immune sentinels to maintain tissue integrity, preserve self-tolerance and protect against invading pathogens. Lung macrophages within the distal ...airways face around 8000⁻9000 L of air every day and for that reason are continuously exposed to a variety of inhaled particles, allergens or airborne microbes. Chronic exposure to irritant particles can prime macrophages to mediate a smoldering inflammatory response creating a mutagenic environment and favoring cancer initiation. Tumor-associated macrophages (TAMs) represent the majority of the tumor stroma and maintain intricate interactions with malignant cells within the tumor microenvironment (TME) largely influencing the outcome of cancer growth and metastasis. A number of macrophage-centered approaches have been investigated as potential cancer therapy and include strategies to limit their infiltration or exploit their antitumor effector functions. Recently, strategies aimed at targeting IL-1 signaling pathway using a blocking antibody have unexpectedly shown great promise on incident lung cancer. Here, we review the current understanding of the bridge between TAM metabolism, IL-1 signaling, and effector functions in lung adenocarcinoma and address the challenges to successfully incorporating these pathways into current anticancer regimens.
Abstract
Fluorizoline is a prohibitin-binding compound that triggers apoptosis in several cell lines from murine and human origin, as well as in primary cells from hematologic malignancies by ...inducing the integrated stress response and ER stress. Recently, it was described that PHB (Prohibitin) 1 and 2 are crucial mitophagy receptors involved in mediating the autophagic degradation of mitochondria. We measured mitophagy in HeLa cells expressing Parkin and in A549, a lung cancer cell line that can undergo mitophagy in a Parkin-independent manner, and we demonstrated that both fluorizoline and rocaglamide A, another PHB-binding molecule, inhibit CCCP- and OA-induced mitophagy. Moreover, we demonstrated that PHBs are mediating Parkin-dependent mitophagy. In conclusion, besides being a potent pro-apoptotic compound, we present fluorizoline as a promising new mitophagy modulator that could be used as anticancer agent.
Calreticulin (CALR) exposure on the cell surface is known to deliver robust pro-phagocytic signals to myeloid cells. In Nature, Sen Santara et al. demonstrate that surface-exposed CALR also operates ...as an endogenous activator of natural killer (NK) cells. Collectively, these findings suggest that CALR exposure orchestrates multiple facets of innate immunosurveillance.
Calreticulin (CALR) exposure on the cell surface is known to deliver robust pro-phagocytic signals to myeloid cells. In Nature, Sen Santara et al. demonstrate that surface-exposed CALR also operates as an endogenous activator of natural killer (NK) cells. Collectively, these findings suggest that CALR exposure orchestrates multiple facets of innate immunosurveillance.
Mitochondrial control of inflammation Marchi, Saverio; Guilbaud, Emma; Tait, Stephen W G ...
Nature reviews. Immunology,
03/2023, Letnik:
23, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Numerous mitochondrial constituents and metabolic products can function as damage-associated molecular patterns (DAMPs) and promote inflammation when released into the cytosol or extracellular ...milieu. Several safeguards are normally in place to prevent mitochondria from eliciting detrimental inflammatory reactions, including the autophagic disposal of permeabilized mitochondria. However, when the homeostatic capacity of such systems is exceeded or when such systems are defective, inflammatory reactions elicited by mitochondria can become pathogenic and contribute to the aetiology of human disorders linked to autoreactivity. In addition, inefficient inflammatory pathways induced by mitochondrial DAMPs can be pathogenic as they enable the establishment or progression of infectious and neoplastic disorders. Here we discuss the molecular mechanisms through which mitochondria control inflammatory responses, the cellular pathways that are in place to control mitochondria-driven inflammation and the pathological consequences of dysregulated inflammatory reactions elicited by mitochondrial DAMPs.
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