Evidence Of Macrophage Activation Research Articles

Possible mediators of metabolic endotoxemia in women with obesity and women with obesity-diabetes in The Gambia

Aims/hypothesisTranslocation of bacterial debris from the gut causes metabolic endotoxemia (ME) that results in insulin resistance, and may be on the causal pathway to obesity-related type 2 diabetes. To guide interventions against ME we tested two hypothesised mechanisms for lipopolysaccharide (LPS) ingress: a leaky gut and chylomicron-associated transfer following a high-fat meal.MethodsIn lean women (n = 48; fat mass index (FMI) 9.6 kg/m2), women with obesity (n = 62; FMI 23.6 kg/m2) and women with obesity-diabetes (n = 38; FMI 24.9 kg/m2) we used the lactulose-mannitol dual-sugar permeability test (LM ratio) to assess gut integrity. Markers of ME (LPS, EndoCAb IgG and IgM, IL-6, CD14 and lipoprotein binding protein) were assessed at baseline, 2 h and 5 h after a standardised 49 g fat-containing mixed meal. mRNA expression of markers of inflammation, macrophage activation and lipid metabolism were measured in peri-umbilical adipose tissue (AT) biopsies.ResultsThe LM ratio did not differ between groups. LPS levels were 57% higher in the obesity-diabetes group (P < 0.001), but, contrary to the chylomicron transfer hypothesis, levels significantly declined following the high-fat challenge. EndoCAb IgM was markedly lower in women with obesity and women with obesity-diabetes. mRNA levels of inflammatory markers in adipose tissue were consistent with the prior concept that fat soluble LPS in AT attracts and activates macrophages.Conclusions/interpretationRaised levels of LPS and IL-6 in women with obesity-diabetes and evidence of macrophage activation in adipose tissue support the concept of metabolic endotoxemia-mediated inflammation, but we found no evidence for abnormal gut permeability or chylomicron-associated post-prandial translocation of LPS. Instead, the markedly lower EndoCAb IgM levels indicate a failure in sequestration and detoxification.

Abstract 1535: Hospicells (MSCs and TAFs relative cells) activate ovarian carcinoma cells and macrophages to secrete IL-6, IL-8 and VEGF and polarize macrophages into a TAM phenotype.

Abstract Epithelial Ovarian carcinoma (EOC) is the leading cause of death from gynaecological cancer in the world and is characterized by peritoneal dissemination, ascite development and a high rate of mortality. Late EOC is treated by a cytoreductive surgery and chemotherapy but most of patients experience a recurrence with the apparition of a chemoresistance. The microenvironment could be implied in this recurrence and the resistance to chemotherapies. Rafii et al. isolated a new type of peritoneal cells from ascitic fluid of patients with stage IIIc ovarian cancer, called Hospicells. These cells share homologies with Mesenchymal Stem Cells (MSCs) and Tumor-associated Fibroblasts (TAFs). Ovarian cancer cells (OCCs) xenograft (i.p. or s.c.) associated with Hospicells in Nude mice leads to a dramatic increase of tumour volume, production of ascitic fluid and mortality. In order to understand these effects, we studied the interactions between OCCs and Hospicells. In vitro, Hospicells and OCCs co-culture leads to the enhancement of the secretion of IL-6, IL-8 and VEGF (cytokines implied in several tumoral processes) by the OCCs compared to the culture of each cell line separately. Moreover, the in vivo co-implantation of Hospicells with OCCs into Nude mice leads to an increase quantity of these cytokines compare to the implantation of OCCs alone. These data suggest a specific crosstalk between OCCs and Hospicells. However, while Hospicells always enhance ovarian cancer progression in vivo, only some cell lines can be activated by Hospicells in vitro. We searched for another Hospicells’ cell partner in vivo and showed that they activate macrophages to polarize into a pro-tumoral tumor-associated phenotype (TAM) and to secrete IL-6, IL-8, VEGF, GM-CSF, IL-1 (α and β), MCP-1, etc… To our knowledge, this is the first evidence of macrophage activation by TAF or MSC-like cells. As ovarian cancer enhanced progression could be due to interactions between OCCs, macrophages and Hospicells, we investigated the pathways potentially implied in the activation of OCCs or macrophages by Hospicells. We already know that TNF-α, IL-1α, estrogens, LPA, S1P or NO pathways are not implied in the activation of OCCs or macrophages by Hospicells but Fas-Ligand, IL-1β or CD40 Ligand pathways are still under investigation. However, we showed that the induction of VEGF secretion in OCCs and macrophages by Hospicells is dependant of the COX-2 pathway. This data strengthens the importance of the inflammatory microenvironment in the ovarian cancer and explain a part of the observed effects of Hospicells on the ovarian cancer progression. Targeting interactions between Hospicells and OCCs and macrophages has potential to improve ovarian cancer treatment efficiency. Citation Format: Benoît Thibault, Magali Castells, Eliane Mery, Jean Pierre Delord, Bettina Couderc. Hospicells (MSCs and TAFs relative cells) activate ovarian carcinoma cells and macrophages to secrete IL-6, IL-8 and VEGF and polarize macrophages into a TAM phenotype. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1535. doi:10.1158/1538-7445.AM2013-1535

Evidence of macrophage activation in Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAs)

Evidence of macrophage activation in Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAs)

Gene delivery to mitotic and postmitotic photoreceptors Via compacted DNA nanoparticles results in improved phenotype in a mouse model of retinitis pigmentosa

The purpose of the present study was to test the therapeutic efficiency and safety of compacted-DNA nanoparticle-mediated gene delivery into the subretinal space of a juvenile mouse model of retinitis pigmentosa. Nanoparticles containing the mouse opsin promoter and wild-type mouse Rds gene were injected subretinally into mice carrying a haploinsufficiency mutation in the retinal degeneration slow (rds(+ or -)) gene at postnatal day (P)5 and 22. Control mice were either injected with saline, injected with uncompacted naked plasmid DNA carrying the Rds gene, or remained untreated. Rds mRNA levels peaked at postinjection day 2 to 7 (PI-2 to PI-7) for P5 injections, stabilized at levels 2-fold higher than in uninjected controls for both P5 and P22 injections, and remained elevated at the latest time point examined (PI-120). Rod function (measured by electroretinography) showed modest but statistically significant improvement compared with controls after both P5 and P22 injections. Cone function in nanoparticle-injected eyes reached wild-type levels for both ages of injections, indicating full prevention of cone degeneration. Ultrastructural examination at PI-120 revealed significant improvement in outer segment structures in P5 nanoparticle-injected eyes, while P22 injection had a modest structural improvement. There was no evidence of macrophage activation or induction of IL-6 or TNF-alpha mRNA in P5 or P22 nanoparticle-dosed eyes at either PI-2 or PI-30. Thus, compacted-DNA nanoparticles can efficiently and safely drive gene expression in both mitotic and postmitotic photoreceptors and retard degeneration in this model. These findings, using a clinically relevant treatment paradigm, illustrate the potential for application of nanoparticle-based gene replacement therapy for treatment of human retinal degenerations.-Cai, X., Conley, S. M., Nash, Z., Fliesler, S. J., Cooper, M. J., Naash, M. I. Gene delivery to mitotic and postmitotic photoreceptors via compacted DNA nanoparticles results in improved phenotype in a mouse model of retinitis pigmentosa.

MyD88-dependent but Toll-like receptor 2-independent innate immunity to Listeria: no role for either in macrophage listericidal activity.

We have assessed the requirements for Toll-like receptor (TLR) signaling in vivo during early infection with Listeria monocytogenes. Mice deficient for TLR2, a receptor required for the recognition of Gram-positive peptidoglycan, showed equivalent Listeria resistance to wild-type mice. However, mice deficient for MyD88, an adaptor molecule used by all TLRs, showed profound susceptibility with 3-4 logs greater Listeria burden and severe spleen and liver pathology at day 3 postinfection. Listeria-infected MyD88-deficient mice also showed markedly diminished IFN-gamma, TNF-alpha, and NO responses, despite evidence of macrophage activation and up-regulation of MHC class II molecules. We demonstrate that although minor MyD88-independent responses to live Listeria do occur, these are insufficient for normal host defense. Lastly, we performed experiments in vitro in which macrophages deficient in TLR2 or MyD88 were directly infected with Listeria: Although TLR signaling was required for macrophage NO and cytokine production in response to Listeria, handling and direct killing of Listeria by activated macrophages occurred by TLR2- and MyD88-independent mechanisms.

Coronary sinus sampling of cytokines after heart transplantation: Evidence for macrophage activation and interleukin-4 production within the graft

Objectives. This study was undertaken to evaluate the organ-specific release of cytokines after heart transplantation and to assess any correlation with transplant rejection. This cytokine profile should document the relative activation of mononuclear cell subsets within the graft.Background. Up to 60% of mononuclear cell infiltrating the cardiac allograft during rejection are macrophages, but their rote is undetermined. The T lymphocytes are activated, but the activity of specific T cell subsets is not known. We sought to assess for the first time in humans the in vivo activation of mononuclear cell subsets by measuring coronary sinus cytokine levels after heart transplantation.Methods. Palred superior vena cava and coronary sinus serum samples were assayed for interkeukin (IL)-2, IL-4 and IL-6, soluble IL-2 receptors, tumor necrosis factor-alpha and neopterin in 10 patients at the time of 40 routine endomyocardial biopsy procedures. All cytokine measurements were made by using enzyme-linked immunosorbent assay; neopterin was measured by using radioimmunoassy.Results. Interleukin-2 levels were not detectable (<0.8 U/ml) in either the superior vena cava or the coronary sinus in the presence or absence of rejection. Interleukin-2 receptor levels were uniformly elevated to 1,283 U/ml in the superior vena cava and to 1,232 U/ml in the coronary sinus, with no correlation with rejection severity. Interleukin-4 levels were consistently higher in coronary sinus serum than in peripheral blood (229 vs. 61 pg/ml, p < O.0005), but there was no relation with rejection. Interleukin-6 levels were higher in the coronary sinus than in me superior vena cava (200 vs. 120 pg/mi, p < 0.05). Tumor necrosis factor-alpha showed consistently elevated levels in coronary sinus serum (68 vs. 17 pg/ml, p < 0.0005), with no relation with rejection. Neopterin, which is produced only by activated macro-phages, was also consistently elevated in the coronary sinus (2.5 vs. 2.2 nmol, p = 0.08).Conclusions. The cardiac allograft is a major source of cyto-kines after heart transplantation. The cytokine profile allows the activity of subsets of the mononuclear cell infiltrate to be investigated. Elevated coronary sinus activity of the macrophage specific metabolite neopterin suggests macrophage activation within the allograft. This possibility is supported by elevated coronary sinus levels of tumor necrosis factor-alpha and IL-6. The T lymphocytes are activated, as evidenced by high soluble IL-2 receptor levels, but IL-2 production was suppressed by conventional immunosup-pressive therapy. Coronary sinus IL-4 levels represent T helper-2 cell activation within the graft despite immunosuppression. We could find no temporal relation between the coronary sinus or superior vena cava cytokine concentration or profile and severity of rejection on concurrent biopsy studies.

The effect of liver macrophages on in vitro cytolytic activity of 5FU and FUdR on colon carcinoma cells: evidence of macrophage activation.

While investigating the effects of 5-fluorouracil (5FU) and 5-fluoro-2'-deoxyuridine (FUdR) on the tumoricidal state of rat liver macrophages activated in vitro by means of liposome-encapsulated muramyl dipeptide (MDP), we observed that 5FU in combination with macrophages produced substantially higher extents of cytolytic activity on tumor cells than 5FU alone. In contrast, FUdR failed to produce this effect; rather, at relatively low FUdR concentrations, lytic activity in the presence of macrophages was even significantly diminished as compared with FUdR in the absence of macrophages. Both 5FU and FUdR were able to enhance the cytolytic activity of macrophages activated by liposome-encapsulated MDP. This finding indicates that, rather than inhibiting the activation of macrophages by liposomal MDP, 5FU can act as a stimulator of macrophage activation by itself. This is further supported by the observations that (i) in combination with 5FU, the secretion of TNF induced by liposomal MDP was synergistically enhanced and (ii) that a second treatment of macrophages with the drug, 24 h after the first, fails to produce increased macrophage cytotoxicity. Our results also show that neither 5FU nor FUdR are likely to unfavorably influence the induction of cytotoxic activity of the macrophages. Rather, combinations of 5FU or FUdR and liposomal MDP may result in an additive or synergistic tumoricidal effect.

Immunomodulation by a low-virulence, agerminative variant ofCandida albicans. Further evidence for macrophage activation as one of the effector mechanisms of nonspecific anti-infectious protection

Systemic infection of mice with a Candida albicans strain (PCA-2) incapable of yeast-mycelial conversion is known to activate host macrophages and confer protection against subsequent challenge with highly pathogenic cells of the same species or by other micro-organisms. In an attempt to define the relative contributions of different immune components to the protection mediated by PCA-2, we evaluated the effect of manipulations known to selectively deplete immune functions. By means of cytostatic drug or silica induced toxicity, it was possible to demonstrate that no crucial role in protection is played by cytotoxic T lymphocytes or B cells, nor by PCA-2 induced granulocytosis alone. The cells responsible for this effect were dacarbazine-resistant silica-sensitive macrophages whose activity in vivo paralleled the in vitro expression of splenic candidacidal activity. Macrophage activation by PCA-2 and increased anti-Candida resistance did not result from an immunological response mediated by T-dependent effectors, as these effects could be reproduced in athymic mice.

The effect of paraquat lung on mononuclear cells

The mouse footpad swelling test was used to clarify the possibility of the induction of local cellular reaction with cell suspension of mouse lungs treated with paraquat in a syngeneous animal. Among the inbred strains used, the highest, statistically significant cellular reactivity was observed in C3H/He strain mice. These results suggest indirect evidence of macrophage activation in the lung toxicity of paraquat.