DigitalUM :: Browsing by Subject "Macrophages"

Browsing by Subject "Macrophages"

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Open Access
Abnormalities in dendritic cell and macrophage accumulation in the pancreas of nonobese diabetic (NOD) mice during the early neonatal period
(Murcia : F. Hernández, 2002) Charré, S.; Rosmalen, J.G.M.; Pelegri, C.; Alves, V.; Leenen, P.J.M.; Drexhage, H.A.; Homo-Delarche, F.
Dendritic cell (DC), macrophage (Mø) and l y m p h o cyte infiltrations have been observed in normal human perinatal pancreata, but have never been investigated so early in control mice. In type 1 diabetesprone NOD mice, these cells are thought to infiltrate first the periphery of the islets of Langerhans around weaning before further islet infiltration and ß-cell destruction. We quantified, during the first month of life, the numbers of DC (characterized by CD11c positivity and dendritic morphology), histiocyte-like Mø (characterized by ER-MP23 positivity) and Mø with scave n g i n g potential (characterized by BM8 positivity) in C57BL/6, DBA/2 and BALB/c control, and NOD and lymphocytedeficient NODscid mouse pancreata. First, CD11c+ DC were present at low densities from birth onwards in control pancreata, while densities were higher in NOD and NODscid. Second, high numbers of BM8+ and ER-MP23+ Mø were observed at birth in all strains investigated. After birth, particularly BM8+ cells disappeared progressively in control strains, but not in NOD and NODs c i d. Third, NOD mice also had more E R - M P 2 3+ Mø at birth compared to controls. Finally, DC and Mø localizations were similar in all strains, i.e., mostly as dispersed cells in periva s c u l a r, periductular, peri-islet areas and interlobular septa. The most remarkable finding was that particularly BM8+ Mø, were seen at sites of islet neogenesis and predominantly at the duct-islet interface. Our data showed that different types of APC were present in the pancreas during postnatal development in various control mouse strains and some differences were o b s e r ved in NOD and NOD s c i d mice from birth onwards.
Open Access
An overview of the structural and functional aspects of immune cells in teleosts
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2021) Mokhtar, Doaa M.; Abdelhafez, Enas A.
The immune system of fish consists of two main components, innate and adaptive immunities. Innate immunity is non-specific and acts as the primary line of protection against pathogen invasion, while adaptive immunity is more specific to a certain pathogen/following adaptation. The adaptive immune system consists of the humoral and cellular components. Cytotoxic T-lymphocyte cells are the major component of the cellular immunity that frequently kills viral-, bacterial- or parasitic-infected cells. According to the anatomical location, the mucosal-associated lymphoid tissue (MALT) in teleost fish subdivides into gutassociated lymphoid tissue (GALT), gill-associated lymphoid tissue (GIALT), and skin-associated lymphoid tissue (SALT). The MALTs contain various leukocytes; including, but not limited to, lymphocytes (T and B cells), plasma cells, macrophages, and granulocytes. Macrophages are multifunctional cells that are mainly involved in the immune response, including; phagocytosis and degradation of foreign antigens, tissue remodeling, and production of cytokines, chemokines and growth factors. An interesting feature of teleost macrophages is their ability to form melanomacrophage centers (MMC) in the hemopoietic tissues. Dendritic cells, rodlet cells, mast cells, eosinophilic granular cells (ECGs), telocytes, osteoclasts, club cells, as well as, barrier cells have been recorded in many fish species and have many immunological roles. This paper aims to summarize the current knowledge of the immune cells present in fish tissues serving as anatomical and physiological barriers against external hazards. Increased knowledge of fish immune systems will facilitate the development of novel vaccination strategies in fish.
Open Access
CD14 release induced by P2X7 receptor restrict inflammation and increases survival during sepsis
(eLife Sciences Publications, 2020-11-26) Alarcón-Vila, Cristina; Baroja-Mazo, Alberto; Torre-Minguela, Carlos de; Martínez-García, Juan J.; Martínez-Banaclocha, Helios; Gracia-Palenciano, Carlos; Martínez Cáceres, Carlos Manuel; Pelegrín Vivancos, Pablo; Bioquímica y Biología Molecular B e Inmunología
P2X7 receptor activation induces the release of different cellular proteins, such as CD14, a glycosylphosphatidylinositol (GPI)-anchored protein to the plasma membrane important for LPS signaling via TLR4. Circulating CD14 has been found at elevated levels in sepsis, but the exact mechanism of CD14 release in sepsis has not been established. Here we show for first time that P2X7 receptor induces the release of CD14 in extracellular vesicles, resulting in a net reduction in macrophage plasma membrane CD14 that functionally affects LPS, but not monophosphoryl lipid A, pro-inflammatory cytokine production. Also, we found that during a murine model of sepsis, P2X7 receptor activity is important for maintaining elevated levels of CD14 in biological fluids and a decrease in its activity results in higher bacterial load and exacerbated organ damage, ultimately leading to premature deaths. Our data reveal that P2X7 is a key receptor for helping to clear sepsis because it maintains elevated concentrations of circulating CD14 during infection.
Open Access
Crescentic glomerulonephritis - a manifestation of a nephritogenic Thl response?
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2000) Kitching, A.R.; Holdsworth, S. R.; Tipping, P. G.
Crescentic glomerulonephritis (GN) is the histopathological correlate of the clinical syndrome of rapidly progressive glomerulonephritis. Glomerular crescent formation complicates proliferative forms of GN and indicates severe disease with a poor renal prognosis. In the past 10 years evidence from experimental models of GN and from human disease has accumulated suggesting that crescentic glomerulonephritis is a manifestation of a delayed type hypersensitivity (DTH)-like response to nephritogenic antigens. The elucidation of T helper 1 (Thl) and Th2 subsets in mice and in humans has led to the hypothesis that crescentic GN is a manifestation of a Thl predominant DTH mediated immune response. Recent experiments performed mainly in a murine model of crescentic glomerulonephritis have tested this hypothesis. Crescent formation in this model is substantially interleukin (IL)-12 and interferon-y (IFN-y) dependent. Administration of IL-12, deletion of endogenous IL-4 or IL-lO results in enhanced disease , while administration of exogenous IL-4 and/or IL-IO reduces crescentic injury. These findings, together with the available evidence from human studies (examining the pattern of immune effectors in glomeruli, data on cytokine production by peripheral blood mononuclear cells and case reports of the induction of proliferative and/or crescentic GN by administration of IFN-y or IL2) suggest that human crescentic GN is manifestation of a Thl mediated DTH-like nephritogenic immune response.
Open Access
Cultured macrophages cause dissolucytosis of metallic silver
(Murcia : F. Hernández, 2009) Jansons Locht, Linda; Larsen, Agnete; Stoltenberg, Meredin; Danscher, Gorm
The present study proves that cultured macrophages can liberate silver ions from metallic silver surfaces by a process called dissolucytosis. Macrophages (J774) were grown on a silver plate for different periods of time and after fixation in glutaraldehyde, they were subjected to autometallograhy in order to amplify possible cellular silver-sulphur nanocrystals. Light and electron microscopic analysis of the cells revealed that silver ions released from the plate had been taken up by the macrophages and accumulated in lysosome- like structures. We found that the liberation of silver ions takes place extracellularly and is caused by chemical activity in a dissolution membrane, most likely secreted and organized by the macrophages. The liberation and the subsequent uptake of silver ions in the macrophages is a relatively fast process and the resulting silver-sulphur nanocrystals can be observed in macrophages that have been in contact with metallic silver for only a few minutes. Our findings indicate that the speed of dissolucytosis is highly influenced by the chemical nature of the object exposed to the dissolucytotic process which is likely to occur whenever macrophages encounter a non-phagocytosable foreign object.
Open Access
Detection of CX3CR1 single nucleotide polymorphism and expression on archived eyes with age-related macular degeneration
(Murcia : F. Hernández, 2005) Chan, C.C.; Tuo, J.; Bojanowski, C.M.; Csaky, K.G.; Green, W.R.
There is a significant genetic component in age-related macular degeneration (AMD). CX3CR1, which encodes the fractalkine (chemokine, CX3CL1) receptor, has two single nucleotide polymorphisms (SNPs): V249I and T280M. These SNPs are correlated with other aged-related diseases such as atherosclerosis. We have reported an association of CX3CR1 SNP and AMD. In this study we examined CX3CR1 SNP frequencies and protein expression on archived sections of AMD and normal eyes. We microdissected nonretinal, peripheral retinal and macular cells from archived slides of eyes of AMD patients and normal subjects. CX3CR1 SNP typing was conducted by PCR and restriction fragment length polymorphism analysis. CX3CR1 transcripts from retinal cells were also measured using RT-PCR. CX3CR1 protein expression was evaluated using avidin-biotin complex immunohistochemistry. We successfully extracted DNA from 32/40 AMD cases and 2/2 normal eyes. Among the 32 AMD cases, 18 had neovascular AMD and 14 had non-neovascular AMD. The M280 allele was detected in 19/64 (32 cases x2) with a frequency of 29.7%, which was significantly higher as compared to the frequency in the normal population (11.2%). We detected CX3CR1 expression in the various retinal cells. CX3CR1 transcript and protein levels were diminished in the macular lesions. This study successfully analyzed CX3CR1 SNP and transcript expression in microdissected cells from archived paraffin fixed slides. Our data suggest that the M280 allele, a SNP resulting in aberrant CX3CR1 and CX3CL1 interaction, as well as lowered expression of macular CX3CR1, may contribute to the development of AMD.
Open Access
Detection of PR-39, a porcine host defence peptide, in different cell sub-linages in pigs infected with Actinobacillus pleuropneumoniae
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Gabner, S.; Egerbacher, M.; Gasse, H.; Hewicker Trautwein, M.; Höltig, D.; Waldmann, K. H.; Blecha, F.; Saalmüller, A.; Hennig Pauka, I.
Innate immunity is critically important for the outcome of infection in many diseases. It was previously shown that cathelicidin PR-39, an important porcine multifunctional host defence peptide, is elevated in bronchoalveolar lavage fluid and respiratory tract tissue after experimental infection with Actinobacillus pleuropneumoniae (A.pp.). To date, neutrophil polymorphonuclear leukocytes (PMNs) are thought to be the only source of PR-39. The aim of this study was to further characterize PR39+ cells and selected immune cell populations in lung tissue during the peracute (7-10 hours), acute (2 days), reconvalescent (7 days) and chronic (21 days) stages of experimental infection with A.pp. serotype 2. In total, six mock-infected control pigs and 12 infected pigs were examined. Using immunofluorescence double-labeling, antibodies against PR-39 were combined with antibodies against CD3 (T-cells), CD79 (B-cells), Iba1 (activated macrophages), TTF-1 (lung epithelial cells expressing surfactant proteins), macrophage/L1 protein and myeloperoxidase (MPO, cells of the myeloid linage). In the peracute and acute phases of infection, total PR-39+ cells and myeloid linage cells increased, whereas CD3+ cells and TTF-1+ cells decreased. Double labeling revealed that most Macrophage/L1 protein+ cells and to a lesser extent MPO+ cells co-expressed PR-39. In addition, few bronchial epithelial cells and type 2 alveolar epithelial cells (both identified with TTF-1) produced PR-39. Occasionally, CD3+ T cells expressing PR-39 were seen in infected animals. Taken together, this study identifies cell types, other than PMNs, in lungs of A.pp.-infected pigs that are capable of producing PR-39. In addition, these findings provide further insights into the dynamics of different immune cell populations during A.pp.-infection.
Open Access
Determinants of axonal regeneration
(Murcia : F. Hernández, 1997) Frisén, J.
Axons often regrow to their targets and lost functions may be restored after an injury in the peripheral nervous system. In contrast, axonal regeneration is generally very limited after injuries in the central nervous system, and functional impairment is usually permanent. The regenerative capacity depends on intrinsic neuronal factors as weil as the interaction of neurons with other cells. Glial cells may, in different situations, either support or inhibit axonal growth. This review discusses the molecular mechanisms that are involved in promoting and inhibiting axonal regeneration in the nervous system after injuries.
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Evolutionary conserved pro-inflammatory and antigen presentation functions of zebrafish IFN revealed by transcriptomic and functional analysis
(Elsevier, 2011-02-26) Azucena López-Munoz; López Muñoz, Azucena; Sepulcre Cortés, María Pilar; Roca Soler, Francisco José; Figueras, Antonio; Meseguer, José; Mulero Méndez, Victoriano Francisco; Biología Celular e Histología
In mammals, IFNγ is the only type II IFN member, whereas most bony fish species have two IFNγ genes, namely IFNγ1 and IFNγ2. We report that both zebrafish IFNγ genes were unable to protect zebrafish larvae against viral infection, despite the fact that they moderately induced the expression of antiviral genes, strongly induced pro-inflammatory and antigen processing and presentation genes, and increased neutrophil numbers. Although both zebrafish IFNγs induced a similar set of immune genes, IFNγ1 was more powerful at inducing pro-inflammatory genes than IFNγ2, which correlated with its ability to promote larval death. Strikingly, IFNγ1-induced larval death was prevented by genetic ablation of the myeloid transcription factor SPI1 but not IL-1β or TNFα, suggesting that professional phagocytes are also one of the main targets of IFNγ in fish. In addition, the usefulness of the zebrafish for the identification of IFNγ-target genes is illustrated by the identification of several genes whose expression is also regulated in murine macrophages by IFNγ, namely two membrane-spanning 4-domain family members and the opioid growth factor receptor. Finally, we found for the first time that the thymic specific proteasome subunit PSMB11/β5t is regulated by IFNγ. Collectively, our data throw light on partially redundant functions of fish IFNγ genes, demonstrate that the pro-inflammatory and antigen presentation functions of IFNγ have been conserved during vertebrate evolution, and highlight the fact that zebrafish is an excellent model for studying IFNγ biology.
Open Access
Extracellular ATP activates the NLRP3 inflammasome and is an early danger signal of skin allograft rejection
(Elsevier, 2017-12-19) Amores Iniesta, Joaquín; Barberá Cremades, María; Parrilla, Pascual; Baroja Mazo, Alberto; Martínez Cáceres, Carlos Manuel; Pelegrín Vivancos, Pablo; Anatomía y Anatomía Patológica Comparadas
Immune cells are equipped with a number of receptors that recognize sterile injury and pathogens. We find that host immune cells release ATP as an inflammatory signal in response to allogeneic transplantation. ATP then acts via a feedback mechanism on the P2X7 channel to activate the NLRP3 inflammasome and subsequently process and release interleukin (IL)-18. This process is a necessary stage in the deleterious Th1 response against allotransplantation via interferon-γ production. Lack of IL-18 resulted in a decrease in graft-infiltrating CD8 cells but an increase in regulatory T cells. In human liver transplant patients undergoing progressive immunosuppressive drug withdrawal, we found that patients experiencing acute rejection had higher levels of the P2X7 receptor in circulating inflammatory monocytes compared to tolerant patients. These data suggest that the pharmacological inhibition of the P2X7 receptor or the NLRP3 inflammasome will aid in inducing transplant tolerance without complete immunoparalysis.
Open Access
Frontotemporal dementia-associated protein "phosphorylated TDP-43" localizes to atherosclerotic lesions of human carotid and main cerebral arteries
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) Umahara, Takahiko; Uchihara, Toshiki; Hirao, Kentaro; Shimizu, Soichiro; Hashimoto, Takao; Akimoto, Jiro; Kohno, Michihiro; Hanyu, Haruo
The transactivation response DNA binding protein (TARDP) of 43 kDa (TDP-43) is a nuclear protein pivotal in RNA processing. Because phosphorylated (p) TDP-43 has been identified as a component of ubiquitin-positive and tau-negative inclusions in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), it is considered to play a major role in neurodegenerative processes. We investigated the immunolocalization of pTDP-43 in atherosclerotic lesions of human carotid and main cerebral arteries. Furthermore, we investigated the co- localization between pTDP-43 and 14-3-3 eta isoform or high mobility group box 1 (HMGB1). pTDP-43 localized in the cytoplasm of many foamy macrophages located in the periphery of lipid-rich necrotic cores, and in the cytoplasm of infiltrated smooth muscle cell-like cells. pTDP-43 co-localized the 14-3-3 eta isoform in carotid plaques. pTDP-43 also co- localized HMGB1. This is the first demonstration of pTDP-43 immunolocalization in human carotid and main cerebral artery plaques. We believe that demonstration of the localization of pTDP-43 in atherosclerotic lesions is important as this may contribute to the establishment of the clinical diagnostic imaging of FTLD and ALS using the pTDP-43 epitope. Moreover, this finding may be useful for further understanding the role of TDP in cell death.
Open Access
Gasdermins mediate cellular release of mitochondrial DNA during pyroptosis and apoptosis
(Wiley, 2021-08) Torre-Minguela, Carlos de; Gomez, Ana I.; Couillin, Isabelle; Pelegrín Vivancos, Pablo; Bioquímica y Biología Molecular B e Inmunología
Pyroptosis and intrinsic apoptosis are two forms of regulated cell death driven by active caspases where plasma membrane permeabilization is induced by gasdermin pores. Caspase-1 induces gasdermin D pore formation during pyroptosis whereas caspase-3 promotes gasdermin E pore formation during apoptosis. These two types of cell death are accompanied by mitochondrial outer membrane permeabilization due to BAK/BAX pore formation in the external membrane of mitochondria, and to some extent this complex also affects the inner mitochondrial membrane facilitating mitochondrial DNA relocalisation from the matrix to the cytosol. However, the detailed mechanism responsible for this process has not been investigated. Herein, we reported that gasdermin processing is required to induce mitochondrial DNA release from cells during pyroptosis and apoptosis. Gasdermin targeted at the plasma membrane promotes a fast mitochondrial collapse along with the initial accumulation of mitochondrial DNA in the cytosol and then facilitates the DNA’s release from the cell when the plasma membrane ruptures. These findings demonstrate that gasdermin action has a critical effect on the plasma membrane and facilitates the release of mitochondrial DNA as a damage-associated molecular pattern.
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Glycoconjugate expression on the cell wall of tps1/tps1 trehalose-deficient Candida albicans strain and implications for its interaction with macrophages
(Oxford University Press, 2011-01-20) Vitse-Standaert, Annie; García-Peñarrubia, Pilar; Argüelles, Juan Carlos; Poulain, Daniel; Jouault, Thierry; Martínez-Esparza Alvargonzález, María Concepción; Tapia Abellán, Ana; Bioquímica y Biología Molecular B e Inmunología
The yeast Candida albicans has developed a variety of strategies to resist macrophage killing. In yeasts, accumulation of trehalose is one of the principal defense mechanisms under stress conditions. The gene-encoding trehalose-6-phosphate synthase (TPS1), which is responsible for trehalose synthesis, is induced in response to oxidative stress, as in phagolysosomes. Mutants unable to synthesize trehalose are sensitive to oxidative stress in vitro. In mice, the TPS1-deficient strain, tps1/tps1, displays a lower infection rate than its parental strain (CAI4). We have previously demonstrated the reduced binding capacity of tps1/tps1 and its lower resistance to macrophages. At the same time, its outer cell wall layer was seen to be altered. In this study, we show that depending on the culture conditions, the tps1/tps1 strain regulates the carbohydrate metabolism in a different way to CAI4, as reflected by the enhanced β-mannosylation of cell wall components, especially at the level of the 120 kDa glycoprotein species, accessible at the cell surface of tps1/tps1 when cultured in liquid medium, but not on solid medium. This leads to changes in its surface properties, as revealed by decreased hydrophobicity, and the lower levels of ERK1/2 phosphorylation and tumor necrosis factor-α (TNF-α) production in macrophages, thus increasing the resistance to these cells. In contrast, in solid medium, in which over-glycosylation was less evident, tps1/tps1 showed similar macrophage interaction properties to CAI4, but was less resistant to killing, confirming the protective role of trehalose. Thus, the lack of trehalose is compensated by an over-glycosylation of the cell wall components in the tps1/tps1 mutant, which reduces susceptibility to killing.
Open Access
Human osteoclast ontogeny and pathological bone resorption
(Murcia : F. Hernández, 1999) Athanasou, N.A.; Sabokbar, A.
Monocytes and macrophages are capable of degrading both the mineral and organic components of bone and are known to secrete local factors which stimulate host osteoclastic bone resorption. Recent studies have shown that monocytes and macrophages, including those isolated from neoplastic and inflammatory lesions, can also be induced to differentiate into cells that show all the cytochemical and functional characteristics of mature osteoclasts, including lacunar bone resorption. Monocyte/macrophage- osteoclast differentiation occurs in the presence of osteoblasts/bone stromal cells (which express osteoclast differentiation factor) and macrophage-colony stimulating factor and is inhibited by osteoprotegerin. Various systemic hormones and local factors (eg cytokines, growth factors, prostaglandins) modulate osteoclast formation by controlling these cellular and humoral elements. Various pathological lesions of bone and joint (eg carcinomatous metastases, arthritis, aseptic loosening) are associated with osteolysis. These lesions generally contain a chronic inflammatory infiltrate in which macrophages form a significant fraction. One cellular mechanism whereby pathological bone resorption may be effected is through generation of increased numbers of bone-resorbing osteoclasts from macrophages. Production of humoral factors which stimulate mononuclear phagocyte-osteoclast differentiation and osteoclast activity is also likely to influence the extent of pathological bone resorption.
Open Access
In vitro effects of hormones and autacoids on the activity of acid phosphatase in the lysates of endotoxin-activated rat peritoneal and bronchoalveolar macrophages
(Murcia : F. Hernández, 2003) Kondomerkos, D.J.; Kalamidas, Stefanos; Kotoulas, Othon B.
Peritoneal and bronchoalveolar macrophages activated in vitro by endotoxin, exhibit alterations in the acid phosphatase activity of cell lysates when certain hormones or autacoids are present in the culture medium. They also show morphological changes concerning general appearance and acid phosphatase cytochemistry. Certain agents known to increase the intracellular levels of cyclic AMP, such as dopamine and prostaglandin E2, decreased this enzyme activity in the lysates of peritoneal macrophages. Adrenalin had no effect on this activity at 14 hours, but was found to increase the activity in the culture medium at the initial hours of incubation. Glucagon decreased whereas insulin increased acid phosphatase activity in bronchoalveolar macrophages. Serotonin or histamine, known to activate phospholipase C, increased this activity in peritoneal or bronchoalveolar macrophages. The results of this study, taken together with previously published data (Kondomerkos et al., 2003), suggest that hormones and autacoids may control certain parameters of macrophage activation including acid phosphatase activity.
Open Access
Inflammatory cells induce neointimal growth in a rat arterial autograft model
(Murcia : F. Hernández, 2002) Jurado, F.; Bellón, J.M.; Rodríguez, M.; Corrales, C.; Buján, J.
Subendothelial invasion by leukocytes is a sign of intimal thickening in arteriosclerosis and in the response of a vessel to mechanical damage. Our study was designed to establish whether these cells are implicated in the formation of a neointima in an autologous arterial graft model in the rat and to evaluate the effects of cyclosporin A (CsA). Three study groups were established according to whether the animals were treated with CsA-Cp (Sandimmun)®, CsA-Et (ethanol vehicle) or received no treatment (control group). Both drug forms were administered (5 mg/kg/day, s.c.) from 4 days prior to surgery until the time of sacrifice. Antibodies specific for lymphocytes (CD4, CD8), monocytes/macrophages-ED1, smooth muscle a-actin and the von Willebrand factor (vWF) were used to identify the cells in the grafted arterial wall. In control grafts, the neointima had formed by 2 weeks postimplant. However, the cells comprising this layer generally presented no positivity whatsoever towards the antibodies employed. At 50 days, the new layer was observed to be formed by a vWF-positive endothelium and a-actin-positive cells. In all three groups, several polymorphonuclear (PMN) cells adhered to the denuded luminal surface from 7 days onwards. In the treated animals, neutrophils and monocytes were seen to infiltrate intimal and medial layers during the later postimplant stages. Around the third week post-implant, the neointima had reached the grafted segment from the distal portion of the recipient artery, and by 50 days it was similar to that seen in control specimens. Our findings suggest that: a) neutrophils play a role in neointimal thickening in this arterial autograft model; and b) CsA promotes the adhesion and infiltration of neutrophils in the injured arterial wall.
Open Access
Inflammatory status in human hepatic cirrhosis
(Baishideng publishing Group, 2015-11-07) Tristán-Manzano, María; García-Peñarrubia, Pilar; Martínez-Esparza Alvargonzález, María Concepción; Ruiz Alcaraz, Antonio José; Bioquímica y Biología Molecular B e Inmunología
This review focuses on new findings about the inflammatory status involved in the development of human liver cirrhosis induced by the two main causes, hepatitis C virus (HCV) infection and chronic alcohol abuse, avoiding results obtained from animal models. When liver is faced to a persistent and/or intense local damage the maintained inflammatory response gives rise to a progressive replacement of normal hepatic tissue by non-functional fibrotic scar. The imbalance between tissue regeneration and fibrosis will determine the outcome toward health recovery or hepatic cirrhosis. In all cases progression toward liver cirrhosis is caused by a dysregulation of mechanisms that govern the balance between activation/homeostasis of the immune system. Detecting differences between the inflammatory status in HCV-induced vs alcohol-induced cirrhosis could be useful to identify specific targets for preventive and therapeutic intervention in each case. Thus, although survival of patients with alcoholic cirrhosis seems to be similar to that of patients with HCV-related cirrhosis (HCV-C), there are important differences in the altered cellular and molecular mechanisms implicated in the progression toward human liver cirrhosis. The predominant features of HCV-C are more related with those that allow viral evasion of the immune defenses, especially although not exclusively, inhibition of interferons secretion, natural killer cells activation and T cell-mediated cytotoxicity. On the contrary, the inflammatory status of alcohol-induced cirrhosis is determined by the combined effect of direct hepatotoxicity of ethanol metabolites and increases of the intestinal permeability, allowing bacteria and bacterial products translocation, into the portal circulation, mesenteric lymph nodes and peritoneal cavity. This phenomenon generates a stronger pro-inflammatory response compared with HCV-related cirrhosis. Hence, therapeutic intervention in HCV-related cirrhosis must be mainly focused to counteract HCV-immune system evasion, while in the case of alcohol-induced cirrhosis it must try to break the inflammatory loop established at the gut-mesenteric lymph nodes-peritoneal-systemic axis.
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Influence of adult Anguillicoloides crassus load in European eels swimbladder on macrophage response
(Elsevier, 2015) Muñoz, Pilar; Peñalver, José; Ruiz de Ybanez, R.; Garcia, J.; Sanidad Animal
Anguillicoloides crassus has become one of the most important threats to the European eel (Anguilla anguilla). Adult parasites colonize the swimbladder leading to an impaired functioning of this organ. The infection is also responsible for an increased in the stress level of infected eels, that could produce an altered immune response as well. Differences in parasite loads and effects in the European and Japanese eel (Anguilla japonica) have been described. We have studied the influence of the number of adult parasites present in the swimbladder of wild eels on the macrophage response (phagocytosis and respiratory burst) as part of the first immune response to pathogens. Our results show an increased phagocytozed bacterial survival 24 h post-infection in macrophages of eels infected with more than ten adult parasites compared to macrophages from eels infected with less than those ten adult parasites. Respiratory burst results also showed a less efficient response in macrophages from eels infected with more than ten adult parasites, although in this case results were not found to be significant.
Open Access
Inhibition of muscle fibrosis and improvement of muscle histopathology in dysferlin knock-out mice treated with halofuginone
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2013) Halevy, Orna; Genin, Olga; Barzilai-Tutsch, Hila; Pima, Yaniv; Levi, Oshrat; Moshe, Itai; Pines, Mark
Absence of, or loss-of-function mutations in the dysferlin gene (dysf) result in dysferlinopathy, characterized by increased muscle inflammation, collagen deposition and deterioration in muscle function. We evaluated halofuginone efficacy in improving muscle histopathology in mice with deleted dysf transmembrane domain. Quadriceps sublumbar and longissimus muscles of 9-month-old dysf-/- mice treated with halofuginone for 4 months exhibited a reduction in centrally-nucleated myofibers, inflammatory infiltrates and collagen content. Late onset of dysferlinopathy makes it ideal for evaluating the efficacy of early treatments on late outcome. The dysf-/- mice were treated with halofuginone for 3 to 4 months starting at 1, 5 or 9 months of age, and quadricep muscle histopathology was evaluated at 12 months. Collagen content and number of centrally nucleated myofibers decreased after early halofuginone treatment, administered when myofibers with central nuclei and inflammatory infiltrates are evident, but there was almost no fibrosis. When administered at the beginning of fibrosis it resulted in a further decrease in the number of centrally-nucleated myofibers with no additional decrease in collagen levels. Cardiac fibrosis was almost completely abolished following early halofuginone treatment. Halofuginone inhibited Smad3 phosphorylation and its translocation to the nucleus and increased the activity of matrix metalloproteinases 9 and 2 responsible for resolution of pre-existing collagen. Macrophage and myofibroblast invasion into the dystrophic muscle at the site of myofibers with central nuclei was inhibited by halofuginone. These results suggest that early halofuginone treatment can prevent the late outcome of dysferlinopathy and can cause resolution of the established fibrosis when administered at later stages.
Open Access
Intracellular signaling modifications involved in the anti-inflammatory effect of 4-alkoxy-6,9-dichloro[1,2,4]triazolo[4,3-a]quinoxalines on macrophages
(Elsevier, 2017-01-03) Tristán-Manzano, María; Guirado, Antonio; Gálvez, Jesús; García-Peñarrubia, Pilar; Martínez-Esparza Alvargonzález, María Concepción; Ruiz Alcaraz, Antonio José; Bioquímica y Biología Molecular B e Inmunología
Inflammation is part of a complex biological response directed by the immune system to fight pathogens and maintain homeostasis. Dysregulation of the inflammatory process leads to development of chronic inflammatory or autoimmune diseases. Several cell types, such as macrophages, and cytokines such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) are involved in the regulation of inflammation. The important role played by these cytokines asmediators of the inflammatory process and the side effects of current therapies have promoted the search of new therapeutic alternatives. Quinoxalines are important compounds allowing a wide range of chemical modifications in order to provide an extensive repertoire of biological activities. We have previously shown that a series of 4-alkoxy-6,9-dichloro[1,2,4]triazolo[4,3-a]quinoxalines exhibit potent anti-inflammatory activity, inhibiting the production of TNF-α and IL-6. Our aim here was to study the mechanism thereby this series of compounds act upon different intracellular signaling pathways to uncover their potential molecular targets. By using immunoblotting assays, we found that these compounds inhibit ERK 1/2 and JNK/c-Jun cascades, and reduce c-Fos expression, while activate the anti-inflammatory PI3K/Akt route. These results provide further information on their effect upon the intracellular signal transduction mechanisms leading to inhibition of TNF-α and IL-6 secretion. Our results may be of great interest for the pharmaceutical industry, and could be used as a starting point for the development of new and more potent anti-inflammatory drugs derived from the quinoxaline core.