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Arginase 1 (Arg1), the enzyme catalyzing the conversion of arginine to ornithine, is a hallmark of IL-10-producing immunoregulatory M2 macrophages. However, its expression in T cells is disputed. Here, we demonstrate that induction of Arg1 expression is a key feature of lung CD4+ T cells during mouse in vivo influenza infection. Conditional ablation of Arg1 in CD4+ T cells accelerated both virus-specific T helper 1 (Th1) effector responses and its resolution, resulting in efficient viral clearance and reduced lung pathology. Using unbiased transcriptomics and metabolomics, we found that Arg1-deficiency was distinct from Arg2-deficiency and caused altered glutamine metabolism. Rebalancing this perturbed glutamine flux normalized the cellular Th1 response. CD4+ T cells from rare ARG1-deficient patients or CRISPR-Cas9-mediated ARG1-deletion in healthy donor cells phenocopied the murine cellular phenotype. Collectively, CD4+ T cell-intrinsic Arg1 functions as an unexpected rheostat regulating the kinetics of the mammalian Th1 lifecycle with implications for Th1-associated tissue pathologies.
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Arginase , Influenza Humana , Animais , Humanos , Camundongos , Arginase/genética , Arginase/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Glutamina , Cinética , Pulmão/metabolismo , MamíferosRESUMO
Coordinative chain transfer polymerization, CCTP, is a degenerative chain transfer polymerization process that has a wide range of applications. It allows a highly controlled synthesis of polyolefins, stereoregular polydienes, and stereoregular polystyrene, including (stereo)block as well as statistical copolymers thereof. It also shows a green character by allowing catalyst economy during the synthesis of such polymers. CCTP notably allows the end functionalization of both the commodity and stereoregular specialty polymers aforementionned, control of the composition of statistical copolymers without adjusting the feed, and quantitative formation of 1-alkenes from ethene. A one-pot one-step synthesis of the original multiblock microstructures and architectures by chain shuttling polymerization (CSP) is also an asset of CCTP. This methodology takes advantage of the simultaneous presence of two catalysts of different selectivity toward comonomers that produce blocks of different composition/microstructure, while still allowing the chain transfer. This affords the production of highly performant functional polymers, such as thermoplastic elastomers and adhesives, among others. This approach has been extended to cyclic esters' and ethers' ring-opening polymerization, providing new types of multiblock microstructure. The present Review provides the state of the art in the field with a focus on the last 10 years.
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Malignant cells are part of a complex network within the tumor microenvironment, where their interaction with host cells and soluble mediators, including complement components, is pivotal. The complement system, known for its role in immune defense and homeostasis, exhibits a dual effect on cancer progression. This dichotomy arises from its antitumoral opsonophagocytosis and cytotoxicity versus its protumoral chronic inflammation mediated by the C5a/C5aR1 axis, influencing antitumor T-cell responses. Recent studies have revealed distinct co-expression patterns of complement genes in various cancer types, correlating with prognosis. Notably, some cancers exhibit co-regulated overexpression of complement genes associated with poor prognosis, while others show favorable outcomes. However, significant intra-patient heterogeneity further complicates this classification. Moreover, the involvement of locally produced and intracellular complement proteins adds complexity to the tumor microenvironment dynamics. This review highlights the unique interplay of complement components within different cancers and patient cohorts, showing that "one size does not fit all", for complement in cancer. It summarizes the clinical trials for complement targeting in cancer, emphasizing the need for tailored therapeutic approaches. By elucidating the mechanistic basis of complement's context-dependent role, this review aims to facilitate the development of personalized cancer therapies, ultimately improving patient care and outcomes.
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Haemolytic disorders, such as sickle cell disease, are accompanied by the release of high amounts of labile heme into the intravascular compartment resulting in the induction of proinflammatory and prothrombotic complications in affected patients. In addition to the relevance of heme-regulated proteins from the complement and blood coagulation systems, activation of the TLR4 signalling pathway by heme was ascribed a crucial role in the progression of these pathological processes. Heme binding to the TLR4-MD2 complex has been proposed recently, however, essential mechanistic information of the processes at the molecular level, such as heme-binding kinetics, the heme-binding capacity and the respective heme-binding sites (HBMs) is still missing. We report the interaction of TLR4, MD2 and the TLR4-MD2 complex with heme and the consequences thereof by employing biochemical, spectroscopic, bioinformatic and physiologically relevant approaches. Heme binding occurs transiently through interaction with up to four HBMs in TLR4, two HBMs in MD2 and at least four HBMs in their complex. Functional studies highlight that mutations of individual HBMs in TLR4 preserve full receptor activation by heme, suggesting that heme interacts with TLR4 through different binding sites independently of MD2. Furthermore, we confirm and extend the major role of TLR4 for heme-mediated cytokine responses in human immune cells.
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Transdução de Sinais , Receptor 4 Toll-Like , Humanos , Receptor 4 Toll-Like/metabolismo , Sítios de Ligação , Citocinas/metabolismo , Antígeno 96 de Linfócito/metabolismo , LipopolissacarídeosRESUMO
A new hybrid catalyst consisting of cobalt nanoparticles immobilized onto cellulose was developed. The cellulosic matrix is derived from date palm biomass waste, which was oxidized by sodium periodate to yield dialdehyde and was further derivatized by grafting orthoaminophenol as a metal ion complexing agent. The new hybrid catalyst was characterized by FT-IR, solid-state NMR, XRD, SEM, TEM, ICP, and XPS. The catalytic potential of the nanocatalyst was then evaluated in the catalytic hydrogenation of 4-nitrophenol to 4-aminophenol under mild experimental conditions in aqueous medium in the presence of NaBH4 at room temperature. The reaction achieved complete conversion within a short period of 7 min. The rate constant was calculated to be K = 8.7 × 10-3 s-1. The catalyst was recycled for eight cycles. Furthermore, we explored the application of the same catalyst for the hydrogenation of cinnamaldehyde using dihydrogen under different reaction conditions. The results obtained were highly promising, exhibiting both high conversion and excellent selectivity in cinnamyl alcohol.
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Hemolytic diseases are frequently linked to multiorgan failure subsequent to vascular damage. Deciphering the mechanisms leading to organ injury upon hemolytic event could bring out therapeutic approaches. Complement system activation occurs in hemolytic disorders, such as sickle cell disease, but the pathological relevance and the acquisition of a complement-activating phenotype during hemolysis remain unclear. Here we found that intravascular hemolysis, induced by injection of phenylhydrazine, resulted in increased alanine aminotransferase plasma levels and NGAL expression. This liver damage was at least in part complement-dependent, since it was attenuated in complement C3-/- mice and by injection of C5-blocking antibody. We evidenced C3 activation fragments' deposits on liver endothelium in mice with intravascular hemolysis or injected with heme as well as on cultured human endothelial cells (EC) exposed to heme. This process was mediated by TLR4 signaling, as revealed by pharmacological blockade and TLR4 deficiency in mice. Mechanistically, TLR4-dependent surface expression of P-selectin triggered an unconventional mechanism of complement activation by noncovalent anchoring of C3 activation fragments, including the typical fluid-phase C3(H2O), measured by surface plasmon resonance and flow cytometry. P-selectin blockade by an antibody prevented complement deposits and attenuated the liver stress response, measured by NGAL expression, in the hemolytic mice. In conclusion, these results revealed the critical impact of the triad TLR4/P-selectin/complement in the liver damage and its relevance for hemolytic diseases. We anticipate that blockade of TLR4, P-selectin, or the complement system could prevent liver injury in hemolytic diseases like sickle cell disease.
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Endotélio Vascular/metabolismo , Heme/metabolismo , Hemólise , Selectina-P/metabolismo , Receptor 4 Toll-Like/metabolismo , Alanina Transaminase/sangue , Anemia Falciforme , Animais , Ativação do Complemento , Complemento C3/metabolismo , Modelos Animais de Doenças , Inativação Gênica , Hemólise/efeitos dos fármacos , Humanos , Lipocalina-2/metabolismo , Fígado/lesões , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenil-Hidrazinas/antagonistas & inibidores , Transdução de Sinais , Receptor 4 Toll-Like/efeitos dos fármacos , Receptor 4 Toll-Like/genéticaRESUMO
Aluminas are strategic materials used in many major industrial processes, either as catalyst supports or as catalysts in their own right. The transition alumina γ-Al2 O3 is a privileged support, whose reactivity can be tuned by thermal activation. This study provides a qualitative and quantitative assessment of the hydroxyl groups present on the surface of γ-Al2 O3 at three different dehydroxylation temperatures. The principal [AlOH] configurations are identified and described in unprecedented detail at the molecular level. The structures were established by combining information from high-field 1 H and 27 Al solid-state NMR, IR spectroscopy and DFT calculations, as well as selective reactivity studies. Finally, the relationship between the hydroxyl structures and the molecular-level structures of the active sites in catalytic alkane metathesis is discussed.
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The well-defined silica-supported molybdenum oxo alkyl species (≡SiO-)MoO(CH2tBu)3 was selectively prepared by grafting of MoO(CH2tBu)3Cl onto partially dehydroxylated silica (silica700) using the surface organometallic chemistry approach. This surface species was fully characterized by elemental analysis and DRIFT, solid-state NMR, and EXAFS spectroscopy. This new material is related to the active species of industrial supported MoO3/SiO2 olefin metathesis catalysts. It displays very high activity in propene self-metathesis at mild (turnover number = 90â¯000 after 25 h). Remarkably, its catalytic performance outpaces those of the parent imido derivative and its tungsten oxo analogue.
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Ring opening metathesis polymerization (ROMP) of bicyclo[2.2.1]hept-2-ene (norbornene) is carried out over silica-supported catalysts based on tungsten complexes bearing an oxo ligand (1: [(SiO)W(O)(CH2 SiMe3 )3 , 2: [(SiO)W(O)(CHCMe2 Ph)(dAdPO)], dAdPO  2,6 diadamantyl-4-methylphenoxide, 3: [(SiO)2 W(O)(CH2 SiMe3 )2 ]). The evaluation of the catalytic activities of the aforementioned materials in ROMP indicates that at low reaction time (0.5 min), the highest polymer yield is obtained with catalyst 2. However, for longer reaction time (>2 min), complex 3, a model of the industrial catalyst, exhibits a better monomer conversion. The polymers obtained are characterized. Moreover, these catalysts are shown to be rather preferentially selective to give the cis polynorbornene (>65%), characterized by high melting points (≈300 °C). The experimental values of the average molecular weight (Mn ) of polynorbornenes are found to be close to the theoretical ones for the polymers prepared using catalyst 2 and higher for those originated from catalyst 3.
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The surface hydroxyl groups of γ-alumina dehydroxylated at 500 °C were studied by a combination of one- and two-dimensional homo- and heteronuclear (1)H and (27)Al NMR spectroscopy at high magnetic field. In particular, by harnessing (1)H-(27) Al dipolar interactions, a high selectivity was achieved in unveiling the topology of the alumina surface. The terminal versus bridging character of the hydroxyl groups observed in the (1)H magic-angle spinning (MAS) NMR spectrum was demonstrated thanks to (1)H-(27) Al RESPDOR (resonance-echo saturation-pulse double-resonance). In a further step the hydroxyl groups were assigned to their aluminium neighbours thanks to a {(1)H}-(27) Al dipolar heteronuclear multiple quantum correlation (D-HMQC), which was used to establish a first coordination map. Then, in combination with (1)H-(1) H double quantum (DQ) MAS, these elements helped to reveal intimate structural features of the surface hydroxyls. Finally, the nature of a peculiar reactive hydroxyl group was demonstrated following this methodology in the case of CO2 reactivity with alumina.
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The grafting of an oxo chloro trisalkyl tungsten derivative on silica dehydroxylated at 700 °C was studied by several techniques that showed reaction via W-Cl cleavage, to afford a well-defined precatalyst for alkene metathesis. This was further confirmed by DFT calculations on the grafting process. (17)O labeling of the oxo moiety of a series of related molecular and supported tungsten oxo derivatives was achieved, and the corresponding (17)O MAS NMR spectra were recorded. Combined experimental and theoretical NMR studies yielded information on the local structure of the surface species. Assessment of the (17)O NMR parameters also confirmed the nature of the grafting pathway by ruling out other possible grafting schemes, thanks to highly characteristic anisotropic features arising from the quadrupolar and chemical shift interactions.
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Flame silica was surface-labeled with (17)O, through isotopic enrichment of both siloxanes and silanols. After heat treatment at 200 and 700 °C under vacuum, the resulting partially dehydroxylated silica materials were investigated by high-field solid-state (1)H and (17)O NMR. More specifically, MQ MAS and HMQC sequences were used to probe the (17)O local environment. In a further step, these (17)O-tagged supports were used for the preparation of supported catalysts by reaction with perhydrocarbyl transition metal derivatives (zirconium tetraalkyl, tantalum trisalkyl-alkylidene, and tungsten trisalkyl-alkylidyne complexes). Detailed (17)O 1D and 2D MQ and HMQC MAS NMR studies demonstrate that signals in the Si-OH, Si-O-Si, and Si-O-metal regions are highly sensitive to local structural modifications, thanks to (17)O wide chemical shift and quadrupolar constant ranges. Experimental results were supported by DFT calculations. From the selective surface labeling, unprecedented information on interactions between supported catalysts and their inorganic carrier has been extracted.
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A green method for the production of cobalt/(TEMPO-Cellulose) aerogel heterogeneous catalyst was developed. The preparation implied the reduction of CoSO4 by NaBH4 in TEMPO-Cellulose water dispersion in ambient conditions. The formation of Cobalt nanoparticles is due to the presence of "TEMPO-Cell" which screens the Co2+ ions and prevents their combination with boron. SEM, XRD, EDX, FTIR, TEM and XPS were used to analyze the structure of the catalyst and showed that metallic cobalt particles have nanometric size and are well dispersed in the aerogel. The catalyst showed excellent activity for model reactions such as the reduction of 4-nitroaniline, 4-nitrophenol and 2-nitrophenol in water, in the presence of NaBH4. The reaction kinetic was studied by UV-visible spectroscopy, which showed that this catalyst is efficient to achieve 100â¯% reduction with high reaction rate and turnover frequency. The aerogel catalyst was reused more than ten times without significant loss of its catalytic activity.
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Nanopartículas Metálicas , Nanocompostos , Catálise , Celulose/química , Cobalto/química , Óxidos N-Cíclicos , Nanopartículas Metálicas/química , Nanocompostos/química , ÁguaRESUMO
Pathway analysis is a key analytical stage in the interpretation of omics data, providing a powerful method for detecting alterations in cellular processes. We recently developed a sensitive and distribution-free statistical framework for multisample distribution testing, which we implement here in the open-source R package single-cell pathway analysis (SCPA). We demonstrate the effectiveness of SCPA over commonly used methods, generate a scRNA-seq T cell dataset, and characterize pathway activity over early cellular activation. This reveals regulatory pathways in T cells, including an intrinsic type I interferon system regulating T cell survival and a reliance on arachidonic acid metabolism throughout T cell activation. A systems-level characterization of pathway activity in T cells across multiple tissues also identifies alpha-defensin expression as a hallmark of bone-marrow-derived T cells. Overall, this work provides a widely applicable tool for single-cell pathway analysis and highlights regulatory mechanisms of T cells.
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Análise de Célula Única , Software , Análise de Célula Única/métodos , Ativação Linfocitária , Sequenciamento do Exoma/métodos , Linfócitos TRESUMO
The complement system, well known for its central role in innate immunity, is currently emerging as an unexpected, cell-autonomous, orchestrator of normal cell physiology. Specifically, an intracellularly active complement system-the complosome-controls key pathways of normal cell metabolism during immune cell homeostasis and effector function. So far, we know little about the exact structure and localization of intracellular complement components within and among cells. A common scheme, however, is that they operate in crosstalk with other intracellular immune sensors, such as inflammasomes, and that they impact on the activity of key subcellular compartments. Among cell compartments, mitochondria appear to have built a particularly early and strong relationship with the complosome and extracellularly active complement-not surprising in view of the strong impact of the complosome on metabolism. In this review, we will hence summarize the current knowledge about the close complosome-mitochondria relationship and also discuss key questions surrounding this novel research area. LINKED ARTICLES: This article is part of a themed issue on Canonical and non-canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc.
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Proteínas do Sistema Complemento , Imunidade Inata , Homeostase , Humanos , Fatores Imunológicos , MitocôndriasRESUMO
Immunologists have recently realized that there is more to the classic innate immune sensor systems than just mere protection against invading pathogens. It is becoming increasingly clear that such sensors, including the inflammasomes, toll-like receptors, and the complement system, are heavily involved in the regulation of basic cell physiological processes and particularly those of metabolic nature. In fact, their "non-canonical" activities make sense as no system directing immune cell activity can perform such task without the need for energy. Further, many of these ancient immune sensors appeared early and concurrently during evolution, particularly during the developmental leap from the single-cell organisms to multicellularity, and therefore crosstalk heavily with each other. Here, we will review the current knowledge about the emerging cooperation between the major inter-cell communicators, integrins, and the cell-autonomous intracellularly and autocrine-active complement, the complosome, during the regulation of single-cell metabolism. LINKED ARTICLES: This article is part of a themed issue on Canonical and non-canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc.
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Proteínas do Sistema Complemento , Integrinas , Humanos , Sistema ImunitárioRESUMO
Neutral and ionic ruthenium and iron aliphatic PNHP-type pincer complexes (PNHP = NH(CH2CH2PiPr2)2) bearing benzyl, n-butyl or tert-butyl isocyanide ancillary ligands have been prepared and characterized. Reaction of [RuCl2(PNHP)]2 with one equivalent CN-R per ruthenium center affords complexes [RuCl2(PNHP)(CNR)] (R = benzyl, 1a, R = n-butyl, 1b, R = t-butyl, 1c), with cationic [RuCl(PNHP)(CNR)2]Cl 2a-c as side-products. Dichloride species 1a-c react with excess NaBH4 to afford [RuH(PNHP)(BH4)(CN-R)] 3a-c, analogues to benchmark Takasago catalyst [RuH(PNHP)(BH4)(CO)]. Reaction of 1a-c with a single equivalent of NaBH4 results in formation of [RuHCl(PNHP) (CN-R)] (4a-c), from which 3a-c can be prepared upon reaction with excess NaBH4. Use of one equivalent of NaHBEt3 with 4a and 4c affords bishydrides [Ru(H)2(PNHP)(CN-R)] 5a and 5c. Deprotonation of 4c by KOtBu generates amido derivative [RuH(PNP)(CN-t-Bu)] (6, PNP = -N(CH2CH2PiPr2)2), unstable in solution. Addition of excess benzylisonitrile to 4a provides cationic hydride [RuH(PNHP) (CN-CH2Ph)2]Cl (7). Concerning iron chemistry, [Fe(PNHP)Br2] reacts with one equivalent of benzylisonitrile to afford [FeBr(PNHP)(CNCH2Ph)2]Br (8). The outer-sphere bromide anion can be exchanged by salt metathesis with NaBPh4 to generate [FeBr(PNHP) (CNCH2Ph)2](BPh4) (9). Cationic hydride species [FeH(PNHP) (CN-t-Bu)2](BH4) (10) is prepared from consecutive addition of excess CN-t-Bu and NaBH4 on [Fe(PNPH)Br2]. Ruthenium complexes 3a-c are active in acceptorless alcohol dehydrogenative coupling into ester under base-free conditions. From kinetic follow-up, the trend in initial activity is 3a ≈ 3b > [RuH(PNHP)(BH4)(CO)] â« 3c; for robustness, [RuH(BH4)(CO)(PNHP)] > 3a > 3b â« 3c. Hypotheses are given to account for the observed deactivation. Complexes 3b, 3c, 4a, 4c, 5c, 7, cis-8 and 9 were characterized by X-ray crystallography.
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Heme's interaction with Toll-like receptor 4 (TLR4) does not fully explain the proinflammatory properties of this hemoglobin-derived molecule during intravascular hemolysis. The receptor for advanced glycation end products (RAGE) shares many features with TLR4 such as common ligands and proinflammatory, prothrombotic, and pro-oxidative signaling pathways, prompting us to study its involvement as a heme sensor. Stable RAGE-heme complexes with micromolar affinity were detected as heme-mediated RAGE oligomerization. The heme-binding site was located in the V domain of RAGE. This interaction was Fe3+ -dependent and competitive with carboxymethyllysine, another RAGE ligand. We confirmed a strong basal gene expression of RAGE in mouse lungs. After intraperitoneal heme injection, pulmonary TNF-α, IL1ß, and tissue factor gene expression levels increased in WT mice but were significantly lower in their RAGE-/- littermates. This may be related to the lower activation of ERK1/2 and Akt observed in the lungs of heme-treated, RAGE-/- mice. Overall, heme binds to RAGE with micromolar affinity and could promote proinflammatory and prothrombotic signaling in vivo, suggesting that this interaction could be implicated in heme-overload conditions.
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Produtos Finais de Glicação Avançada/genética , Heme/genética , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor 4 Toll-Like/genética , Animais , Sítios de Ligação/genética , Heme/metabolismo , Humanos , Interleucina-1beta/genética , Ligantes , Pulmão/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Proteínas Proto-Oncogênicas c-akt/genética , Fator de Necrose Tumoral alfa/genéticaRESUMO
The complement system is a powerful and druggable innate immune component of the tumor microenvironment. Nevertheless, it is challenging to elucidate the exact mechanisms by which complement affects tumor growth. In this study, we examined the processes by which the master complement regulator factor H (FH) affects clear cell renal cell carcinoma (ccRCC) and lung cancer, two cancers in which complement overactivation predicts poor prognosis. FH was present in two distinct cellular compartments: the membranous (mb-FH) and intracellular (int-FH) compartments. Int-FH resided in lysosomes and colocalized with C3. In ccRCC and lung adenocarcinoma, FH exerted protumoral action through an intracellular, noncanonical mechanism. FH silencing in ccRCC cell lines resulted in decreased proliferation, due to cell-cycle arrest and increased mortality, and this was associated with increased p53 phosphorylation and NFκB translocation to the nucleus. Moreover, the migration of the FH-silenced cells was reduced, likely due to altered morphology. These effects were cell type-specific because no modifications occurred upon CFH silencing in other FH-expressing cells tested: tubular cells (from which ccRCC originates), endothelial cells (human umbilical vein endothelial cells), and squamous cell lung cancer cells. Consistent with this, in ccRCC and lung adenocarcinoma, but not in lung squamous cell carcinoma, int-FH conferred poor prognosis in patient cohorts. Mb-FH performed its canonical function of complement regulation but had no impact on tumor cell phenotype or patient survival. The discovery of intracellular functions for FH redefines the role of the protein in tumor progression and its use as a prognostic biomarker or potential therapeutic target.See article by Daugan et al., p. 891 (36).
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Ativação do Complemento/genética , Fator H do Complemento/genética , Animais , Linhagem Celular , Progressão da Doença , Humanos , CamundongosRESUMO
While serum-circulating complement destroys invading pathogens, intracellularly active complement, termed the "complosome," functions as a vital orchestrator of cell-metabolic events underlying T cell effector responses. Whether intracellular complement is also nonredundant for the activity of myeloid immune cells is currently unknown. Here, we show that monocytes and macrophages constitutively express complement component (C) 5 and generate autocrine C5a via formation of an intracellular C5 convertase. Cholesterol crystal sensing by macrophages induced C5aR1 signaling on mitochondrial membranes, which shifted ATP production via reverse electron chain flux toward reactive oxygen species generation and anaerobic glycolysis to favor IL-1ß production, both at the transcriptional level and processing of proIL-1ß. Consequently, atherosclerosis-prone mice lacking macrophage-specific C5ar1 had ameliorated cardiovascular disease on a high-cholesterol diet. Conversely, inflammatory gene signatures and IL-1ß produced by cells in unstable atherosclerotic plaques of patients were normalized by a specific cell-permeable C5aR1 antagonist. Deficiency of the macrophage cell-autonomous C5 system also protected mice from crystal nephropathy mediated by folic acid. These data demonstrate the unexpected intracellular formation of a C5 convertase and identify C5aR1 as a direct modulator of mitochondrial function and inflammatory output from myeloid cells. Together, these findings suggest that the complosome is a contributor to the biologic processes underlying sterile inflammation and indicate that targeting this system could be beneficial in macrophage-dependent diseases, such as atherosclerosis.