RESUMO
BACKGROUND: On-pump cardiac surgery triggers sterile inflammation and postoperative complications such as postoperative atrial fibrillation (POAF). Hematopoietic somatic mosaicism (HSM) is a recently identified risk factor for cardiovascular diseases and results in a shift toward a chronic proinflammatory monocyte transcriptome and phenotype. OBJECTIVES: The aim of this study was to assess the prevalence, characteristics, and impact of HSM on preoperative blood and myocardial myeloid cells as well as on outcomes after cardiac surgery. METHODS: Blood DNA from 104 patients referred for surgical aortic valve replacement (AVR) was genotyped using the HemePACT panel (576 genes). Four screening methods were applied to assess HSM, and postoperative outcomes were explored. In-depth blood and myocardial leukocyte phenotyping was performed in selected patients using mass cytometry and preoperative and postoperative RNA sequencing analysis of classical monocytes. RESULTS: The prevalence of HSM in the patient cohort ranged from 29%, when considering the conventional HSM panel (97 genes) with variant allelic frequencies ≥2%, to 60% when considering the full HemePACT panel and variant allelic frequencies ≥1%. Three of 4 explored HSM definitions were significantly associated with higher risk for POAF. On the basis of the most inclusive definition, HSM carriers exhibited a 3.5-fold higher risk for POAF (age-adjusted OR: 3.5; 95% CI: 1.52-8.03; P = 0.003) and an exaggerated inflammatory response following AVR. HSM carriers presented higher levels of activated CD64+CD14+CD16- circulating monocytes and inflammatory monocyte-derived macrophages in presurgery myocardium. CONCLUSIONS: HSM is frequent in candidates for AVR, is associated with an enrichment of proinflammatory cardiac monocyte-derived macrophages, and predisposes to a higher incidence of POAF. HSM assessment may be useful in the personalized management of patients in the perioperative period. (Post-Operative Myocardial Incident & Atrial Fibrillation [POMI-AF]; NCT03376165).
Assuntos
Fibrilação Atrial , Procedimentos Cirúrgicos Cardíacos , Humanos , Fibrilação Atrial/etiologia , Fibrilação Atrial/genética , Mosaicismo , Valva Aórtica/cirurgia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Fatores de Risco , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/genética , Complicações Pós-Operatórias/diagnósticoRESUMO
A rare but severe complication of curative-intent radiation therapy is the induction of second primary cancers. These cancers preferentially develop not inside the planning target volume (PTV) but around, over several centimeters, after a latency period of 1-40 years. We show here that normal human or mouse dermal fibroblasts submitted to the out-of-field dose scattering at the margin of a PTV receiving a mimicked patient's treatment do not die but enter in a long-lived senescent state resulting from the accumulation of unrepaired DNA single-strand breaks, in the almost absence of double-strand breaks. Importantly, a few of these senescent cells systematically and spontaneously escape from the cell cycle arrest after a while to generate daughter cells harboring mutations and invasive capacities. These findings highlight single-strand break-induced senescence as the mechanism of second primary cancer initiation, with clinically relevant spatiotemporal specificities. Senescence being pharmacologically targetable, they open the avenue for second primary cancer prevention.
Assuntos
Reparo do DNA , Segunda Neoplasia Primária , Animais , Carcinogênese , Transformação Celular Neoplásica , Senescência Celular , Quebras de DNA de Cadeia Simples , Dano ao DNA , CamundongosRESUMO
Retinoic acid receptor-related orphan receptor-alpha (RORα) is a transcription factor from the nuclear receptor family expressed by immune cells and involved in the development of obesity, insulin resistance (IR) and non-alcoholic steatohepatitis (NASH). It was recently reported that mice deficient for RORα in macrophages develop more severe NASH upon high fat diet (HFD) feeding due to altered Kupffer cell function. To better understand the role of RORα in obesity and IR, we independently generated a macrophage RORα-deficient mouse line. We report that RORα deletion in macrophages does not impact on HFD-induced obesity and IR. Surprisingly, we did not confirm an effect on NASH development upon HFD feeding nor in the more severe and obesity-independent choline-deficient, L-amino acid-defined diet model. Our results therefore show that RORα deletion in macrophages does not alter the development of obesity and IR and question its role in NASH.
Assuntos
Resistência à Insulina , Macrófagos/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Obesidade/metabolismo , Animais , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Deleção de Genes , Células de Kupffer/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Obesidade/etiologiaRESUMO
Using brain lymphoma model, we demonstrate that immunotherapy combining Treg depletion (using anti-CD25 mAb PC61) followed by intracranial CpG-ODN administration induced tumor rejection in all treated mice and led to the establishment of a memory antitumor immune response in 60% of them. This protective effect was associated with a recruitment of NK cells and, to a lesser extent, of dendritic cells, B cells and T lymphocytes. NK cell depletion abolished the protective effect of the treatment, confirming a major role of NK cells in brain tumor elimination. Each treatment used alone failed to protect brain tumor bearing mice, revealing the therapeutic benefit of combining Treg depletion and local CpG-ODN injection.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Linfoma/tratamento farmacológico , Oligodesoxirribonucleotídeos/uso terapêutico , Linfócitos T Reguladores/fisiologia , Animais , Anticorpos/toxicidade , Antígenos Ly/imunologia , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Etoposídeo/farmacologia , Etoposídeo/uso terapêutico , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/fisiologia , Linfoma/complicações , Linfoma/metabolismo , Linfoma/patologia , Transtornos da Memória/etiologia , Transtornos da Memória/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Subfamília B de Receptores Semelhantes a Lectina de Células NK/imunologia , Transplante de Neoplasias , Linfócitos T Reguladores/efeitos dos fármacos , Fatores de Tempo , Receptor Toll-Like 9/metabolismoRESUMO
Microglia are the major myeloid-immune cells of the brain parenchyma. In a steady state, microglia monitor their environment for pathogens or damaged cells. In response to neural injury or inflammation, microglia become competent APCs able to prime CD4(+) and CD8(+) T lymphocytes. We previously demonstrated that neonatal and adult microglia cross-present exogenous soluble Ags in vitro. However, whether microglia are able to cross-present Ag to naive CD8(+) T cells in vivo, within the brain microenvironment, remains undetermined. Here, we have designed an original protocol in order to exclude the involvement in cross-presentation activity of peripheral migrating APCs and of CNS-associated APCs. In C57Bl/6 mice, in which the body but not the head has been properly irradiated, we analyzed the ability of resident microglia to stimulate intracerebrally injected CD8(+) T cells in vivo. This study demonstrates for the first time that adult microglia cross-present Ag to naive CD8(+) T cells in vivo and that full microglia activation is required to overcome the inhibitory constrains of the brain and to render microglia able to cross-prime naive CD8(+) T cells injected in the brain. These observations offer new insights in brain-tumor immunotherapy based on the induction of cytotoxic antitumoral T cells.