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1.
Nat Commun ; 13(1): 139, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013270

RESUMO

Oxylipins are potent biological mediators requiring strict control, but how they are removed en masse during infection and inflammation is unknown. Here we show that lipopolysaccharide (LPS) dynamically enhances oxylipin removal via mitochondrial ß-oxidation. Specifically, genetic or pharmacological targeting of carnitine palmitoyl transferase 1 (CPT1), a mitochondrial importer of fatty acids, reveal that many oxylipins are removed by this protein during inflammation in vitro and in vivo. Using stable isotope-tracing lipidomics, we find secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Meanwhile, oxylipin ß-oxidation is uncoupled from oxidative phosphorylation, thus not contributing to energy generation. Testing for genetic control checkpoints, transcriptional interrogation of human neonatal sepsis finds upregulation of many genes involved in mitochondrial removal of long-chain fatty acyls, such as ACSL1,3,4, ACADVL, CPT1B, CPT2 and HADHB. Also, ACSL1/Acsl1 upregulation is consistently observed following the treatment of human/murine macrophages with LPS and IFN-γ. Last, dampening oxylipin levels by ß-oxidation is suggested to impact on their regulation of leukocyte functions. In summary, we propose mitochondrial ß-oxidation as a regulatory metabolic checkpoint for oxylipins during inflammation.


Assuntos
Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Metabolismo dos Lipídeos/genética , Mitocôndrias/efeitos dos fármacos , Oxilipinas/metabolismo , Peritonite/genética , Sepse/genética , Acil-CoA Desidrogenase de Cadeia Longa/sangue , Acil-CoA Desidrogenase de Cadeia Longa/genética , Animais , Carnitina O-Palmitoiltransferase/sangue , Carnitina O-Palmitoiltransferase/genética , Coenzima A Ligases/sangue , Coenzima A Ligases/genética , Feminino , Regulação da Expressão Gênica , Humanos , Recém-Nascido , Interferon gama/farmacologia , Lipidômica/métodos , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Subunidade beta da Proteína Mitocondrial Trifuncional/sangue , Subunidade beta da Proteína Mitocondrial Trifuncional/genética , Oxirredução , Peritonite/sangue , Peritonite/induzido quimicamente , Peritonite/patologia , Células RAW 264.7 , Sepse/sangue , Sepse/patologia
2.
Cells ; 10(2)2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33540679

RESUMO

Metabolism is considered to be the core of all cellular activity. Thus, extensive studies of metabolic processes are ongoing in various fields of biology, including cancer research. Cancer cells are known to adapt their metabolism to sustain high proliferation rates and survive in unfavorable environments with low oxygen and nutrient concentrations. Hence, targeting cancer cell metabolism is a promising therapeutic strategy in cancer research. However, cancers consist not only of genetically altered tumor cells but are interwoven with endothelial cells, immune cells and fibroblasts, which together with the extracellular matrix (ECM) constitute the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), which are linked to poor prognosis in different cancer types, are one important component of the TME. CAFs play a significant role in reprogramming the metabolic landscape of tumor cells, but how, and in what manner, this interaction takes place remains rather unclear. This review aims to highlight the metabolic landscape of tumor cells and CAFs, including their recently identified subtypes, in different tumor types. In addition, we discuss various in vitro and in vivo metabolic techniques as well as different in silico computational tools that can be used to identify and characterize CAF-tumor cell interactions. Finally, we provide our view on how mapping the complex metabolic networks of stromal-tumor metabolism will help in finding novel metabolic targets for cancer treatment.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Contagem de Células , Humanos , Células Tumorais Cultivadas , Microambiente Tumoral
3.
Front Immunol ; 8: 1146, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28993767

RESUMO

Neonates and especially premature infants are highly susceptible to infection but still can have a remarkable resilience that is poorly understood. The view that neonates have an incomplete or deficient immune system is changing. Human neonatal studies are challenging, and elucidating host protective responses and underlying cognate pathway biology, in the context of viral infection in early life, remains to be fully explored. In both resource rich and poor settings, human cytomegalovirus (HCMV) is the most common cause of congenital infection. By using unbiased systems analyses of transcriptomic resources for HCMV neonatal infection, we find the systemic response of a preterm congenital HCMV infection, involves a focused IFN regulatory response associated with dendritic cells. Further analysis of transcriptional-programming of neonatal dendritic cells in response to HCMV infection in culture revealed an early dominant IFN-chemokine regulatory subnetworks, and at later times the plasticity of pathways implicated in cell-cycle control and lipid metabolism. Further, we identify previously unknown suppressed networks associated with infection, including a select group of GPCRs. Functional siRNA viral growth screen targeting 516-GPCRs and subsequent validation identified novel GPCR-dependent antiviral (ADORA1) and proviral (GPR146, RGS16, PTAFR, SCTR, GPR84, GPR85, NMUR2, FZ10, RDS, CCL17, and SORT1) roles. By contrast a gene family cluster of protocadherins is significantly differentially induced in neonatal cells, suggestive of possible immunomodulatory roles. Unexpectedly, programming responses of adult and neonatal dendritic cells, upon HCMV infection, demonstrated comparable quantitative and qualitative responses showing that functionally, neonatal dendritic cell are not overly compromised. However, a delay in responses of neonatal cells for IFN subnetworks in comparison with adult-derived cells are notable, suggestive of subtle plasticity differences. These findings support a set-point control mechanism rather than immaturity for explaining not only neonatal susceptibility but also resilience to infection. In summary, our findings show that neonatal HCMV infection leads to a highly plastic and functional robust programming of dendritic cells in vivo and in vitro. In comparison with adults, a minimal number of subtle quantitative and temporal differences may contribute to variability in host susceptibility and resilience, in a context dependent manner.

4.
Med Microbiol Immunol ; 204(3): 395-407, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25800350

RESUMO

Homeostasis underpins at a systems level the regulatory control of immunity and metabolism. While physiologically these systems are often viewed as independent, there is increasing evidence showing a tight coupling between immune and metabolic functions. Critically upon infection, the homeostatic regulation for both immune and metabolic pathways is altered yet these changes are often investigated in isolation. Here, we summarise our current understanding of these processes in the context of a clinically relevant pathogen, cytomegalovirus. We synthesise from the literature an integrative view of a coupled immune-metabolic infection process, centred on sugar and lipid metabolism. We put forward the notion that understanding immune control of key metabolic enzymatic steps in infection will promote the future development of novel therapeutic modalities based on metabolic modifiers that either enhance protection or inhibit infection.


Assuntos
Interações Hospedeiro-Patógeno , Imunomodulação , Infecções/imunologia , Infecções/metabolismo , Animais , Metabolismo dos Carboidratos/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Humanos , Infecções/terapia , Metabolismo dos Lipídeos/efeitos dos fármacos
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