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1.
Sci Immunol ; 8(86): eadg3517, 2023 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-37566679

RESUMO

The skin needs to balance tolerance of colonizing microflora with rapid detection of potential pathogens. Flexible response mechanisms would seem most suitable to accommodate the dynamic challenges of effective antimicrobial defense and restoration of tissue homeostasis. Here, we dissected macrophage-intrinsic mechanisms and microenvironmental cues that tune macrophage signaling in localized skin infection with the colonizing and opportunistic pathogen Staphylococcus aureus. Early in skin infection, the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by γδ T cells and hypoxic conditions within the dermal microenvironment diverted macrophages away from a homeostatic M-CSF- and hypoxia-inducible factor 1α (HIF-1α)-dependent program. This allowed macrophages to be metabolically rewired for maximal inflammatory activity, which requires expression of Irg1 and generation of itaconate, but not HIF-1α. This multifactorial macrophage rewiring program was required for both the timely clearance of bacteria and for the provision of local immune memory. These findings indicate that immunometabolic conditioning allows dermal macrophages to cycle between antimicrobial activity and protection against secondary infections.


Assuntos
Macrófagos , Infecções Cutâneas Estafilocócicas , Humanos , Citocinas/metabolismo , Transdução de Sinais , Infecções Cutâneas Estafilocócicas/metabolismo
2.
EMBO Rep ; 23(5): e54096, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35357743

RESUMO

Immunoregulation of inflammatory, infection-triggered processes in the brain constitutes a central mechanism to control devastating disease manifestations such as epilepsy. Observational studies implicate the viability of Taenia solium cysts as key factor determining severity of neurocysticercosis (NCC), the most common cause of epilepsy, especially in children, in Sub-Saharan Africa. Viable, in contrast to decaying, cysts mostly remain clinically silent by yet unknown mechanisms, potentially involving Tregs in controlling inflammation. Here, we show that glutamate dehydrogenase from viable cysts instructs tolerogenic monocytes to release IL-10 and the lipid mediator PGE2 . These act in concert, converting naive CD4+ T cells into CD127- CD25hi FoxP3+ CTLA-4+ Tregs, through the G protein-coupled receptors EP2 and EP4 and the IL-10 receptor. Moreover, while viable cyst products strongly upregulate IL-10 and PGE2 transcription in microglia, intravesicular fluid, released during cyst decay, induces pro-inflammatory microglia and TGF-ß as potential drivers of epilepsy. Inhibition of PGE2 synthesis and IL-10 signaling prevents Treg induction by viable cyst products. Harnessing the PGE2 -IL-10 axis and targeting TGF-ß signaling may offer an important therapeutic strategy in inflammatory epilepsy and NCC.


Assuntos
Cistos , Dinoprostona , Criança , Dinoprostona/farmacologia , Humanos , Interleucina-10 , Monócitos , Oxirredutases , Linfócitos T Reguladores
3.
Cell Metab ; 31(6): 1120-1135.e7, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32402266

RESUMO

Anti-obesity drugs in the amphetamine (AMPH) class act in the brain to reduce appetite and increase locomotion. They are also characterized by adverse cardiovascular effects with origin that, despite absence of any in vivo evidence, is attributed to a direct sympathomimetic action in the heart. Here, we show that the cardiac side effects of AMPH originate from the brain and can be circumvented by PEGylation (PEGyAMPH) to exclude its central action. PEGyAMPH does not enter the brain and facilitates SNS activity via theß2-adrenoceptor, protecting mice against obesity by increasing lipolysis and thermogenesis, coupled to higher heat dissipation, which acts as an energy sink to increase energy expenditure without altering food intake or locomotor activity. Thus, we provide proof-of-principle for a novel class of exclusively peripheral anti-obesity sympathofacilitators that are devoid of any cardiovascular and brain-related side effects.


Assuntos
Anfetamina/farmacologia , Fármacos Antiobesidade/farmacologia , Encéfalo/efeitos dos fármacos , Obesidade/tratamento farmacológico , Animais , Encéfalo/metabolismo , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/metabolismo
4.
J Immunol ; 203(12): 3416-3426, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31732532

RESUMO

IFN-ß essentially modulates the host response against mucocutaneous colonizers and potential pathogens, such as group B Streptococcus (GBS). It has been reported that the dominant signaling cascade driving IFN-ß in macrophages (MΦ) in streptococcal infection is the cGAS-STING pathway, whereas conventional dendritic cells (DC) exploit endosomal recognition by intracellular TLRs. In this study, we revisited this issue by precisely monitoring the phenotypic dynamics in mixed mouse MΦ/DC cultures with GM-CSF, which requires snapshot definition of cellular identities. We identified four mononuclear phagocyte populations, of which two were transcriptionally and morphologically distinct MΦ-DC-like subsets, and two were transitional types. Notably, GBS induced a TLR7-dependent IFN-ß signal only in MΦ-like but not in DC-like cells. IFN-ß induction did not require live bacteria (i.e., the formation of cytolytic toxins), which are essential for IFN-ß induction via cGAS-STING. In contrast to IFN-ß, GBS induced TNF-α independently of TLR7. Subsequent to the interaction with streptococci, MΦ changed their immunophenotype and gained some typical DC markers and DC-like morphology. In summary, we identify IFN-ß formation as part of the antistreptococcal repertoire of GM-CSF differentiated MΦ in vitro and in vivo and delineate their plasticity.


Assuntos
Interferon beta/biossíntese , Macrófagos/imunologia , Macrófagos/metabolismo , Streptococcus/imunologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Imunofenotipagem , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Fator Estimulador de Colônias de Macrófagos/farmacologia , Camundongos , Modelos Biológicos , Fagocitose , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/metabolismo , Infecções Estreptocócicas/microbiologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/microbiologia
5.
J Leukoc Biol ; 106(1): 209-218, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30762892

RESUMO

In the healthy brain, microglia and other CNS macrophages are the most abundant immune cell type. Thus, they form the natural immune cell interface with streptococci, which are the leading cause of bacterial meningitis and encephalitis in infants and young children. In homeostasis, the blood-brain barrier allows for very limited access of immune cells circulating in the periphery. During bacterial meningoencephalitis, however, origin and fate of CNS macrophages are massively altered. This review summarizes the emerging knowledge on the sequence of reciprocal events between streptococci and CNS macrophages leading to host resistance, acute inflammation, changes in resident innate immune cells of the brain, and long-term neuronal damage.


Assuntos
Encéfalo/imunologia , Macrófagos/fisiologia , Meningoencefalite/imunologia , Infecções Estreptocócicas/imunologia , Adaptação Fisiológica , Animais , Barreira Hematoencefálica , Humanos , Moléculas com Motivos Associados a Patógenos/farmacologia , Linfócitos T/imunologia
6.
Nat Med ; 23(11): 1309-1318, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29035364

RESUMO

The cellular mechanism(s) linking macrophages to norepinephrine (NE)-mediated regulation of thermogenesis have been a topic of debate. Here we identify sympathetic neuron-associated macrophages (SAMs) as a population of cells that mediate clearance of NE via expression of solute carrier family 6 member 2 (SLC6A2), an NE transporter, and monoamine oxidase A (MAOA), a degradation enzyme. Optogenetic activation of the sympathetic nervous system (SNS) upregulates NE uptake by SAMs and shifts the SAM profile to a more proinflammatory state. NE uptake by SAMs is prevented by genetic deletion of Slc6a2 or inhibition of the encoded transporter. We also observed an increased proportion of SAMs in the SNS of two mouse models of obesity. Genetic ablation of Slc6a2 in SAMs increases brown adipose tissue (BAT) content, causes browning of white fat, increases thermogenesis, and leads to substantial and sustained weight loss in obese mice. We further show that this pathway is conserved, as human sympathetic ganglia also contain SAMs expressing the analogous molecular machinery for NE clearance, which thus constitutes a potential target for obesity treatment.


Assuntos
Macrófagos/metabolismo , Neurônios/metabolismo , Norepinefrina/metabolismo , Obesidade/patologia , Sistema Nervoso Simpático/patologia , Animais , Receptor 1 de Quimiocina CX3C/metabolismo , Perfilação da Expressão Gênica , Homeostase , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Obesidade/genética
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