RESUMO
This meeting report presents a consensus on the biological aspects of lipid emulsions in parenteral nutrition, emphasizing the unanimous support for the integration of lipid emulsions, particularly those containing fish oil, owing to their many potential benefits beyond caloric provision. Lipid emulsions have evolved from simple energy sources to complex formulations designed to improve safety profiles and offer therapeutic benefits. The consensus highlights the critical role of omega-3 polyunsaturated fatty acids (PUFAs), notably eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), found in fish oil and other marine oils, for their anti-inflammatory properties, muscle mass preservation, and as precursors to the specialized pro-resolving mediators (SPMs). SPMs play a significant role in immune modulation, tissue repair, and the active resolution of inflammation without impairing host defense mechanisms. The panel's agreement underscores the importance of incorporating fish oil within clinical practices to facilitate recovery in conditions like surgery, critical illness, or immobility, while cautioning against therapies that might disrupt natural inflammation resolution processes. This consensus not only reaffirms the role of specific lipid components in enhancing patient outcomes, but also suggests a shift towards nutrition-based therapeutic strategies in clinical settings, advocating for the proactive evidence-based use of lipid emulsions enriched with omega-3 PUFAs. Furthermore, we should seek to apply our knowledge concerning DHA, EPA, and their SPM derivatives, to produce more informative randomized controlled trial protocols, thus allowing more authoritative clinical recommendations.
Assuntos
Inflamação , Humanos , Inflamação/metabolismo , Ácidos Graxos Ômega-3/uso terapêutico , Ácidos Graxos Ômega-3/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/efeitos dos fármacos , Ácido Eicosapentaenoico/uso terapêutico , Ácido Eicosapentaenoico/farmacologia , Nutrição Parenteral/métodos , Óleos de Peixe/uso terapêutico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Emulsões Gordurosas Intravenosas/uso terapêutico , AnimaisRESUMO
Lipids are undoubtedly the major constituents of the cell membranes of all living organisms, and the most efficient source of energy [...].
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Doenças Neurodegenerativas , Humanos , Doenças Neurodegenerativas/metabolismo , Membrana Celular/metabolismo , LipídeosRESUMO
Omega-3 (ω-3) polyunsaturated fatty acids, including docosahexaenoic acid (DHA), are involved in numerous biological processes and have a range of health benefits. DHA is obtained through the action of elongases (ELOVLs) and desaturases, among which Elovl2 is the key enzyme involved in its synthesis, and can be further metabolized into several mediators that regulate the resolution of inflammation. Our group has recently reported that ELOVL2 deficient mice (Elovl2-/-) not only display reduced DHA levels in several tissues, but they also have higher pro-inflammatory responses in the brain, including the activation of innate immune cells such as macrophages. However, whether impaired synthesis of DHA affects cells of adaptive immunity, i.e., T lymphocytes, is unexplored. Here we show that Elovl2-/- mice have significantly higher lymphocytes in peripheral blood and that both CD8+ and CD4+ T cell subsets produce greater amounts of pro-inflammatory cytokines in both blood and spleen compared to wild type mice, with a higher percentage of cytotoxic CD8+ T cells (CTLs) as well as IFN-γ-producing Th1 and IL-17-producing Th17 CD4+ cells. Furthermore, we also found that DHA deficiency impacts the cross-talk between dendritic cells (DC) and T cells, inasmuch as mature DCs of Elovl2-/- mice bear higher expression of activation markers (CD80, CD86 and MHC-II) and enhance the polarization of Th1 and Th17 cells. Reintroducing DHA back into the diets of Elovl2-/- mice reversed the exacerbated immune responses observed in T cells. Hence, impairment of endogenous synthesis of DHA exacerbates T cell inflammatory responses, accounting for an important role of DHA in regulating adaptive immunity and in potentially counteracting T-cell-mediated chronic inflammation or autoimmunity.
Assuntos
Ácidos Docosa-Hexaenoicos , Inflamação , Animais , Camundongos , Linfócitos T CD4-Positivos/metabolismo , Citocinas , Ácidos Docosa-Hexaenoicos/metabolismo , Elongases de Ácidos Graxos , Inflamação/imunologia , Inflamação/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Linfócitos T CD8-Positivos/metabolismoRESUMO
Lipid mediators are important regulators in inflammatory responses, and their biosynthetic pathways are targeted by commonly used anti-inflammatory drugs. Switching from pro-inflammatory lipid mediators (PIMs) to specialized pro-resolving (SPMs) is a critical step toward acute inflammation resolution and preventing chronic inflammation. Although the biosynthetic pathways and enzymes for PIMs and SPMs have now been largely identified, the actual transcriptional profiles underlying the immune cell type-specific transcriptional profiles of these mediators are still unknown. Using the Atlas of Inflammation Resolution, we created a large network of gene regulatory interactions linked to the biosynthesis of SPMs and PIMs. By mapping single-cell sequencing data, we identified cell type-specific gene regulatory networks of the lipid mediator biosynthesis. Using machine learning approaches combined with network features, we identified cell clusters of similar transcriptional regulation and demonstrated how specific immune cell activation affects PIM and SPM profiles. We found substantial differences in regulatory networks in related cells, accounting for network-based preprocessing in functional single-cell analyses. Our results not only provide further insight into the gene regulation of lipid mediators in the immune response but also shed light on the contribution of selected cell types in their biosynthesis.
Assuntos
Redes Reguladoras de Genes , Inflamação , Humanos , Inflamação/metabolismo , Eicosanoides , Anti-Inflamatórios , Sistema Imunitário/metabolismoRESUMO
BACKGROUND: Lenabasum is a synthetic cannabinoid receptor type-2 (CB2) agonist able to exert potent anti-inflammatory effects, but its role on T cells remains unknown. OBJECTIVES: The present study was undertaken to investigate anti-inflammatory mechanisms of lenabasum in T lymphocyte subsets and its in vivo therapeutic efficacy in experimental autoimmune encephalomyelitis (EAE). METHODS: Mononuclear cells from 17 healthy subjects (HS) and 25 relapsing-remitting multiple sclerosis (RRMS) patients were activated in presence or absence of lenabasum and analysed by flow cytometry and qRT-PCR. EAE mice were treated with lenabasum, and clinical score and neuroinflammation were evaluated. RESULTS: Lenabasum significantly reduced TNF-a production from CD4+ T cells and CD8+ T cells in a dose-dependent manner in both HS and RRMS patients. In MS patients, lenabasum also reduced activation marker CD25 and inhibited IL-2 production from both T cell subsets and IFN-γ and IL-17 from committed Th1 and Th17 cells, respectively. These effects were blocked by the pretreatment with selective CB2 inverse agonist SR144528. In vivo treatment of EAE mice with lenabasum significantly ameliorated disease severity, reduced neuroinflammation and demyelination in spinal cord. CONCLUSION: Lenabasum exerts potent T cell-mediated immunomodulatory effects, suggesting CB2 as a promising pharmacological target to counteract neuroinflammation in MS.
Assuntos
Anti-Inflamatórios/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Dronabinol/análogos & derivados , Esclerose Múltipla Recidivante-Remitente/imunologia , Receptor CB2 de Canabinoide/agonistas , Subpopulações de Linfócitos T/efeitos dos fármacos , Adulto , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dronabinol/farmacologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Humanos , Masculino , Camundongos , Subpopulações de Linfócitos T/imunologiaRESUMO
Lipids are not only constituents of cellular membranes, but they are also key signaling mediators, thus acting as "bioactive lipids". Among the prominent roles exerted by bioactive lipids are immune regulation, inflammation, and maintenance of homeostasis. Accumulated evidence indicates the existence of a bidirectional relationship between the immune and nervous systems, and lipids can interact particularly with the aggregation and propagation of many pathogenic proteins that are well-renowned hallmarks of several neurodegenerative disorders, including Alzheimer's (AD) and Parkinson's (PD) diseases. In this review, we summarize the current knowledge about the presence and quantification of the main classes of endogenous bioactive lipids, namely glycerophospholipids/sphingolipids, classical eicosanoids, pro-resolving lipid mediators, and endocannabinoids, in AD and PD patients, as well as their most-used animal models, by means of lipidomic analyses, advocating for these lipid mediators as powerful biomarkers of pathology, diagnosis, and progression, as well as predictors of response or activity to different current therapies for these neurodegenerative diseases.
Assuntos
Doença de Alzheimer , Doença de Parkinson , Animais , Eicosanoides , Humanos , Lipidômica , Doença de Parkinson/metabolismo , Esfingolipídeos/metabolismoRESUMO
Docosahexaenoic acid (DHA) is a ω-3 fatty acid typically obtained from the diet or endogenously synthesized through the action of elongases (ELOVLs) and desaturases. DHA is a key central nervous system constituent and the precursor of several molecules that regulate the resolution of inflammation. In the present study, we questioned whether the impaired synthesis of DHA affected neural plasticity and inflammatory status in the adult brain. To address this question, we investigated neural and inflammatory markers from mice deficient for ELOVL2 (Elovl2-/- ), the key enzyme in DHA synthesis. From our findings, Elovl2-/- mice showed an altered expression of markers involved in synaptic plasticity, learning, and memory formation such as Egr-1, Arc1, and BDNF specifically in the cerebral cortex, impacting behavioral functions only marginally. In parallel, we also found that DHA-deficient mice were characterized by an increased expression of pro-inflammatory molecules, namely TNF, IL-1ß, iNOS, caspase-1 as well as the activation and morphologic changes of microglia in the absence of any brain injury or disease. Reintroducing DHA in the diet of Elovl2-/- mice reversed such alterations in brain plasticity and inflammation. Hence, impairment of systemic DHA synthesis can modify the brain inflammatory and neural plasticity status, supporting the view that DHA is an essential fatty acid with an important role in keeping inflammation within its physiologic boundary and in shaping neuronal functions in the central nervous system.
Assuntos
Encéfalo/metabolismo , Ácidos Docosa-Hexaenoicos/biossíntese , Regulação da Expressão Gênica , Microglia/metabolismo , Plasticidade Neuronal , Animais , Biomarcadores/metabolismo , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/genética , Caspase 1/biossíntese , Caspase 1/genética , Ácidos Docosa-Hexaenoicos/genética , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Proteína 1 de Resposta de Crescimento Precoce/genética , Elongases de Ácidos Graxos/deficiência , Elongases de Ácidos Graxos/metabolismo , Inflamação/genética , Inflamação/metabolismo , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Camundongos , Camundongos Knockout , Microglia/patologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genéticaRESUMO
Chronic inflammation is a key pathological hallmark of multiple sclerosis (MS) and suggests that resolution of inflammation, orchestrated by specialized pro-resolving lipid mediators (LM), is impaired. Here, through targeted-metabololipidomics in peripheral blood of patients with MS, we revealed that each disease form was associated with distinct LM profiles that significantly correlated with disease severity. In particular, relapsing and progressive MS patients were associated with high eicosanoids levels, whereas the majority of pro-resolving LM were significantly reduced or below limits of detection and correlated with disease progression. Furthermore, we found impaired expression of several pro-resolving LM biosynthetic enzymes and receptors in blood-derived leukocytes of MS patients. Mechanistically, differentially expressed mediators like LXA4, LXB4, RvD1 and PD1 reduced MS-derived monocyte activation and cytokine production, and inhibited inflammation-induced blood-brain barrier dysfunction and monocyte transendothelial migration. Altogether, these findings reveal peripheral defects in the resolution pathway in MS, suggesting pro-resolving LM as novel diagnostic biomarkers and potentially safe therapeutics.
Assuntos
Monócitos , Esclerose Múltipla , Barreira Hematoencefálica , Eicosanoides , Humanos , Inflamação , Mediadores da Inflamação , Esclerose Múltipla/tratamento farmacológicoRESUMO
Chronic heart failure (CHF) is characterized by an ongoing nonresolving inflammatory status, where T lymphocytes seem critical. It has been recently recognized that transition from acute to chronic inflammation could be caused by defects in resolving inflammation, the resolution of which is mediated by a novel family of ω-3-derived specialized proresolving lipid mediators such as resolvins. We analyzed 27 elderly patients with CHF and 23 healthy age-matched control subjects, and we reported significantly lower levels of D-series resolvin (RvD)1 in plasma of patients with CHF that were associated with a reduced ability of their leukocytes to produce this lipid via its biosynthetic enzyme 15-lipoxygenase and that correlated with gas exchange dysfunction. Furthermore, when pretreating ex vivo peripheral blood mononuclear cells of patients with CHF with RvD1 or RvD2, we found that neither of them was able to modulate the immune response of CD8+ and CD4+ T cells in terms of proinflammatory cytokine production, namely TNF-α, IFN-γ, IL-17, and IL-2. Such impaired T-cell responsiveness in patients with CHF was associated with a significant reduction in mRNA and protein expression of RvD1 receptor GPR32, suggesting a defective signaling in the proresolving pathway. We conclude that patients with CHF show alterations in producing proresolving mediator RvD1 and a failure of adaptive immune cells in responding to the anti-inflammatory actions of RvDs that may contribute to the progression of chronic inflammation. Thus, the proresolution pathway might be a potential candidate to design better treatments for CHF aimed at reducing T cell-mediated chronic inflammation.-Chiurchiù, V., Leuti, A., Saracini, S., Fontana, D., Finamore, P., Giua, R., Padovini, L., Incalzi, R. A., Maccarrone, M. Resolution of inflammation is altered in chronic heart failure and entails a dysfunctional responsiveness of T lymphocytes.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Insuficiência Cardíaca/imunologia , Inflamação/imunologia , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Feminino , Humanos , MasculinoRESUMO
Autacoid local injury antagonist amides (ALIAmides) are a family of endogenous bioactive acyl ethanolamides that include the renowned palmitoyl ethanolamide (PEA), oleoyl ethanolamide (OEA), and stearoyl ethanolamide (SEA), and that are involved in several biologic processes such as nociception, lipid metabolism, and inflammation. The role of ALIAmides in the control of inflammatory processes has recently gained much attention and prompted the use of these molecules or their analogs, and the pharmacologic manipulation of their endogenous levels, as plausible therapeutic strategies in the treatment of several chronic inflammatory conditions. Since chronic inflammation is mainly driven by cells of adaptive immunity, particularly T lymphocytes, we aimed at investigating whether such bioactive lipids could directly modulate T-cell responses. We found that OEA, PEA, and eicosatrienoyl ethanolamide (ETEA) could directly inhibit both T-cell responses by reducing their production of TNF-α and IFN-γ from CD8 T cells and TNF-α, IFN-γ and IL-17 from CD4 T cells. Furthermore, neither SEA nor docosatrienoyl ethanolamide (DTEA) could affect cytokine production from both T cell subsets. Interestingly, unlike OEA and ETEA, PEA was also able to enhance de novo generation of forkhead box P3 (FoxP3)-expressing regulatory T cells from CD4-naive T cells. Our findings show for the first time that specific ALIAmides can directly affect different T-cell subsets, and provide proof of their anti-inflammatory role in chronic inflammation, ultimately suggesting that these bioactive lipids could offer novel tools for the management of T-cell dependent chronic inflammatory diseases.-Chiurchiù, V., Leuti, A., Smoum, R., Mechoulam, R., Maccarrone, M. Bioactive lipids ALIAmides differentially modulate inflammatory responses of distinct subsets of primary human T lymphocytes.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Endocanabinoides/farmacologia , Etanolaminas/farmacologia , Ácidos Oleicos/farmacologia , Ácidos Palmíticos/farmacologia , Ácidos Esteáricos/farmacologia , Amidas , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Citocinas/imunologia , Endocanabinoides/imunologia , Etanolaminas/imunologia , Humanos , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/patologia , Ácidos Oleicos/imunologia , Ácidos Palmíticos/imunologia , Ácidos Esteáricos/imunologiaRESUMO
The endocannabinoid system comprises cannabinoid receptors 1 and 2 (CB1 and CB2), their endogenous ligands, anandamide (AEA) and 2-arachidonoylglycerol, and metabolic enzymes of these ligands. The endocannabinoid system has recently been implicated in the regulation of various pathophysiological processes of the skin that include immune competence and/or tolerance of keratinocytes, the disruption of which might promote the development of skin diseases. Recent evidence showed that CB1 in keratinocytes limits the secretion of proinflammatory chemokines, suggesting that this receptor might also regulate T cell dependent inflammatory diseases of the skin. In this article, we sought to investigate the cytokine profile of IFN-γ-activated keratinocytes, and found that CB1 activation by AEA suppressed production and release of signature TH1- and TH17-polarizing cytokines, IL-12 and IL-23, respectively. We also set up cocultures between a conditioned medium of treated keratinocytes and naive T cells to disclose the molecular details that regulate the activation of highly proinflammatory TH1 and TH17 cells. AEA-treated keratinocytes showed reduced an induction of IFN-γ-producing TH1 and IL-17-producing TH17 cells, and these effects were reverted by pharmacological inhibition of CB1 Further analyses identified mammalian target of rapamycin as a proinflammatory signaling pathway regulated by CB1, able to promote either IL-12 and IL-23 release from keratinocytes or TH1 and TH17 polarization. Taken together, these findings demonstrate that AEA suppresses highly pathogenic T cell subsets through CB1-mediated mammalian target of rapamycin inhibition in human keratinocytes. Thus, it can be speculated that the latter pathway might be beneficial to the physiological function of the skin, and can be targeted toward inflammation-related skin diseases.
Assuntos
Ácidos Araquidônicos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Endocanabinoides/farmacologia , Queratinócitos/fisiologia , Alcamidas Poli-Insaturadas/farmacologia , Dermatopatias/tratamento farmacológico , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Ácidos Araquidônicos/uso terapêutico , Agonistas de Receptores de Canabinoides/uso terapêutico , Diferenciação Celular , Células Cultivadas , Citocinas/metabolismo , Endocanabinoides/uso terapêutico , Humanos , Inflamação/imunologia , Ativação Linfocitária , Terapia de Alvo Molecular , Alcamidas Poli-Insaturadas/uso terapêutico , Receptores de Canabinoides/metabolismo , Dermatopatias/imunologia , Serina-Treonina Quinases TOR/metabolismo , Células Th1/imunologia , Células Th17/imunologiaRESUMO
Docosahexaenoic acid (DHA) is an omega-3 fatty acid obtained from the diet or synthesized from alpha-linolenic acid through the action of fatty acid elongases (ELOVL) and desaturases. DHA plays important roles in the central nervous system as well as in peripheral organs and is the precursor of several molecules that regulate resolution of inflammation. In the present study, we questioned whether impaired synthesis of DHA affected macrophage plasticity and polarization both in vitro and in vivo models. For this we investigated the activation status and inflammatory response of bone marrow-derived M1 and M2 macrophages obtained from mice deficient of Elovl2 (Elovl2-/-), a key enzyme for DHA synthesis in mammals. Although both wild type and Elovl2-/- mice were able to generate efficient M1 and M2 macrophages, M1 cells derived from Elovl2-/- mice showed an increased expression of key markers (iNOS, CD86 and MARCO) and cytokines (IL-6, IL-12 and IL-23). However, M2 macrophages exhibited upregulated M1-like markers like CD80, CD86 and IL-6, concomitantly with a downregulation of their signature marker CD206. These effects were counteracted in cells obtained from DHA-supplemented animals. Finally, white adipose tissue of Elovl2-/- mice presented an M1-like pro-inflammatory phenotype. Hence, impairment of systemic DHA synthesis delineates an alteration of M1/M2 macrophages both in vitro and in vivo, with M1 being hyperactive and more pro-inflammatory while M2 less protective, supporting the view that DHA has a key role in controlling the balance between pro- and anti-inflammatory processes.
Assuntos
Ácidos Docosa-Hexaenoicos/imunologia , Inflamação/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/imunologia , Animais , Polaridade Celular/efeitos dos fármacos , Células Cultivadas , Ácidos Docosa-Hexaenoicos/farmacologia , Inflamação/tratamento farmacológico , Interleucina-12/imunologia , Interleucina-23/imunologia , Interleucina-6/imunologia , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/imunologiaRESUMO
G protein-coupled receptor 55 (GPR55) is activated by endogenous, plant-derived and synthetic cannabinoids. Recent studies reported a broad tissue distribution for GPR55 and found prominent roles for this receptor in inflammatory pain, gut and bone physiology, as well as cancer. However, little is known about the expression and function of GPR55 in immune cells. To address this question, we performed a detailed characterization of GPR55 in different human innate and adaptive immune populations using polychromatic flow cytometry and we found that monocytes and NK cells expressed remarkable levels of this receptor compared to several cells of adaptive immunity. GPR55 activation by the specific agonist O-1602 boosted IL-12 and TNF-α production, and decreased endocytic activity, in LPS-activated monocytes. In addition, it increased CD69 activation marker expression, granzyme B and CD107a-dependent cytotoxicity and IFN-γ and TNF-α production in NK cells activated by both IL-2 and IL-12. These over-stimulatory effects of GPR55 were antagonized by its selective antagonist cannabidiol. Altogether, our data thus unveil a proinflammatory role for GPR55 in innate immunity that may be important for the design of new immune therapeutic strategies.
Assuntos
Células Matadoras Naturais/imunologia , Monócitos/imunologia , Receptores de Canabinoides/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Circulação Sanguínea , Canabidiol/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Células Cultivadas , Cicloexanos/farmacologia , Citocinas/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imunidade Inata , Células Matadoras Naturais/efeitos dos fármacos , Lipopolissacarídeos/imunologia , Ativação Linfocitária/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Receptores de Canabinoides/genética , Receptores Acoplados a Proteínas G/genética , Resorcinóis/farmacologia , TranscriptomaRESUMO
Monocytes are believed to be involved in the immunopathogenesis of multiple sclerosis (MS). The aim of this study was to investigate their role in MS and their immunomodulation by the endocannabinoid system (ECS), a novel target for the treatment of this disease. We compared the level of cytokine production from monocytes in healthy subjects and MS patients upon stimulation with viral or bacterial Toll-like receptors (TLR) and we evaluated the ECS immunomodulatory role in these cells. Here we show that MS monocytes produced more TNF-α, IL-12 and IL-6 following activation of TLR2/4 with LPS or of TLR5 with flagellin, as opposed to TLR7/8 stimulation with R848. Furthermore AEA, the main endocannabinoid, suppressed cytokine production and release from healthy monocytes upon stimulation with both bacterial and viral TLR receptors but not in cells from MS patients, where its immunosuppressive activity was TLR7/8-dependent. Altered expression levels of key ECS members in MS monocytes paralleled these data. Our data disclose a distinct immunomodulatory effect of AEA and an alteration of AEA-related members of the ECS in monocytes from MS patients that involves viral but not bacterial TLR. These findings not only may help to better understand the role of monocytes in MS immunopathogenesis but also could be of help to exploit new endocannabinoid-based drugs that target innate immune cells.
Assuntos
Ácidos Araquidônicos/uso terapêutico , Endocanabinoides/uso terapêutico , Lipídeos/uso terapêutico , Monócitos/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Alcamidas Poli-Insaturadas/uso terapêutico , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo , Adulto , Endocanabinoides/metabolismo , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Imunossupressores/uso terapêutico , Interleucina-12/metabolismo , Interleucina-6/metabolismo , Masculino , Monócitos/metabolismo , Esclerose Múltipla/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The immune system can be modulated and regulated not only by foreign antigens but also by other humoral factors and metabolic products, which are able to affect several quantitative and qualitative aspects of immunity. Among these, endocannabinoids are a group of bioactive lipids that might serve as secondary modulators, which when mobilized coincident with or shortly after first-line immune modulators, increase or decrease many immune functions. Most immune cells express these bioactive lipids, together with their set of receptors and of enzymes regulating their synthesis and degradation. In this review, a synopsis of the manifold immunomodulatory effects of endocannabinoids and their signalling in the different cell populations of innate and adaptive immunity is appointed, with a particular distinction between mice and human immune system compartments.
RESUMO
OBJECTIVE: The immunopathogenesis of multiple sclerosis (MS) has always been thought to be driven by chronically activated and autoreactive Th-1 and Th-17 cells. Recently, dendritic cells (DCs) have also been thought to significantly contribute to antigenic spread and to maturation of adaptive immunity, and have been linked with disease progression and exacerbation. However, the role of DCs in MS pathogenesis remains poorly understood. METHODS: We compared the level of cytokine production by myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in healthy subjects and MS patients, following in vitro stimulation of Toll-like receptors 7/8. We also evaluated the effect of the main endocannabinoid, anandamide (AEA), in these DC subsets and correlated cytokine levels with defects in the endocannabinoid system. RESULTS: mDCs obtained from MS patients produce higher levels of interleukin-12 and interleukin-6, whereas pDCs account for lower levels of interferon-α compared to healthy subjects. AEA significantly inhibited cytokine production from healthy mDCs and pDCs, as well as their ability to induce Th-1 and Th-17 lineages. Moreover, we found that in MS only pDCs lack responsiveness to cytokine inhibition induced by AEA. Consistently, this specific cell subset expresses higher levels of the anandamide hydrolase fatty acid amide hydrolase (FAAH). INTERPRETATION: Our data disclose a distinct immunomodulatory effect of AEA in mDCs and pDCs from MS patients, which may reflect an alteration of the expression of FAAH, thus forming the basis for the rational design of new endocannabinoid-based immunotherapeutic agents targeting a specific cell subset.
Assuntos
Ácidos Araquidônicos , Agonistas de Receptores de Canabinoides , Células Dendríticas/imunologia , Endocanabinoides , Esclerose Múltipla/patologia , Células Mieloides/imunologia , Alcamidas Poli-Insaturadas , Adolescente , Adulto , Idoso , Amidoidrolases/genética , Amidoidrolases/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Células Mieloides/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptor CB2 de Canabinoide/genética , Receptor CB2 de Canabinoide/metabolismo , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismo , Receptor 8 Toll-Like/genética , Receptor 8 Toll-Like/metabolismo , Adulto JovemRESUMO
Endocannabinoids (eCBs) and glucocorticoids (GCs) are two distinct classes of signaling lipids that exert both neuroprotective and immunosuppressive effects; however, the possibility of an actual interaction of their receptors [i.e., type-2 cannabinoid (CB2) and glucocorticoid receptor α (GRα), respectively] remains unexplored. Here, we demonstrate that the concomitant activation of CB2 and GRα abolishes the neuroprotective effects induced by each receptor on central neurons and on glial cells in animal models of remote cell death. We also show that the ability of eCBs and GCs, used individually, to inhibit tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) production from activated human T lymphocytes is lost when CB2 and GRα are activated simultaneously. In addition, signal transduction pathways triggered by concomitant activation of both receptors led to increased levels of GRß, heat-shock proteins-70 and -90, and p-JNK, as well as to reduced levels of p-STAT6. These effects were reversed only by selectively antagonizing CB2, but not GRα. Overall, our study demonstrates for the first time the existence of a CB2-driven negative cross-talk between eCB and GC signaling in both rats and humans, thus paving the way to the possible therapeutic exploitation of CB2 as a new target for chronic inflammatory and neurodegenerative diseases.
Assuntos
Neuroglia/metabolismo , Neurônios/metabolismo , Receptor Cross-Talk/fisiologia , Receptor CB2 de Canabinoide/metabolismo , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/fisiologia , Análise de Variância , Animais , Western Blotting , Endocanabinoides/metabolismo , Citometria de Fluxo , Glucocorticoides/metabolismo , Humanos , Imuno-Histoquímica , Imunoprecipitação , Interferon gama/metabolismo , Masculino , Ratos , Ratos Wistar , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Breast Cancer (BC) is one of the most common tumours, and is known for its ability to develop resistance to chemotherapeutic treatments. Autophagy has been linked to chemotherapeutic response in several types of cancer, highlighting its contribution to this process. However, the role of mitophagy, a selective form of autophagy responsible for damaged mitochondria degradation, in the response to therapies in BC is still unclear. In order to address this point, we analysed the role of mitophagy in the treatment of the most common anticancer drug, doxorubicin (DXR), in different models of BC, such as a luminal A subtype-BC cell line MCF7 cells, cultured in 2-Dimension (2D) or in 3-Dimension (3D), and the triple negative BC (TNBC) cell line MDA-MB-231. Through a microarray analysis, we identified a relationship between mitophagy gene expressions related to the canonical PINK1/Parkin-mediated pathway and DXR treatment in BC cells. Afterwards, we demonstrated that the PINK1/Parkin-dependent mitophagy is indeed induced following DXR treatment and that exogenous expression of a small non-coding RNA, the miRNA-218-5p, known to target mRNA of Parkin, was sufficient to inhibit the DXR-mediated mitophagy in MCF7 and in MDA-MB-231 cells, thereby increasing their sensitivity to DXR. Considering the current challenges involved in BC refractory to treatment, our work could provide a promising approach to prevent tumour resistance and recurrence, potentially leading to the development of an innovative approach to combine mitophagy inhibition and chemotherapy.
RESUMO
Immunometabolism investigates the intricate relationship between the immune system and cellular metabolism. This study delves into the consequences of mitochondrial frataxin (FXN) depletion, the primary cause of Friedreich's ataxia (FRDA), a debilitating neurodegenerative condition characterized by impaired coordination and muscle control. By using single-cell RNA sequencing, we have identified distinct cellular clusters within the cerebellum of an FRDA mouse model, emphasizing a significant loss in the homeostatic response of microglial cells lacking FXN. Remarkably, these microglia deficient in FXN display heightened reactive responses to inflammatory stimuli. Furthermore, our metabolomic analyses reveal a shift towards glycolysis and itaconate production in these cells. Remarkably, treatment with butyrate counteracts these immunometabolic changes, triggering an antioxidant response via the itaconate-Nrf2-GSH pathways and suppressing the expression of inflammatory genes. Furthermore, we identify Hcar2 (GPR109A) as a mediator involved in restoring the homeostasis of microglia without FXN. Motor function tests conducted on FRDA mice underscore the neuroprotective attributes of butyrate supplementation, enhancing neuromotor performance. In conclusion, our findings elucidate the role of disrupted homeostatic function in cerebellar microglia in the pathogenesis of FRDA. Moreover, they underscore the potential of butyrate to mitigate inflammatory gene expression, correct metabolic imbalances, and improve neuromotor capabilities in FRDA.
Assuntos
Frataxina , Ataxia de Friedreich , Succinatos , Animais , Camundongos , Butiratos , Frataxina/genética , Ataxia de Friedreich/genética , Ataxia de Friedreich/metabolismo , Ataxia de Friedreich/patologia , Glucose , Microglia/metabolismoRESUMO
Obesity and type 2 diabetes cause a loss in brown adipose tissue (BAT) activity, but the molecular mechanisms that drive BAT cell remodeling remain largely unexplored. Using a multilayered approach, we comprehensively mapped a reorganization in BAT cells. We uncovered a subset of macrophages as lipid-associated macrophages (LAMs), which were massively increased in genetic and dietary model of BAT expansion. LAMs participate in this scenario by capturing extracellular vesicles carrying damaged lipids and mitochondria released from metabolically stressed brown adipocytes. CD36 scavenger receptor drove LAM phenotype, and CD36-deficient LAMs were able to increase brown fat genes in adipocytes. LAMs released transforming growth factor ß1 (TGF-ß1), which promoted the loss of brown adipocyte identity through aldehyde dehydrogenase 1 family member A1 (Aldh1a1) induction. These findings unfold cell dynamic changes in BAT during obesity and identify LAMs as key responders to tissue metabolic stress and drivers of loss of brown adipocyte identity.