Macrophage Migration Inhibition Research Articles

Effects of macrophage migration inhibitory factor on early acute pancreatitis

To investigate the value of macrophage migration inhibitor factor (MIF) in early severe acute pancreatitis (SAP). (1) Animal experiment: according to the random number table method, 24 male Sprague-Dawley (SD) rats were divided into Sham group and SAP 3, 6 and 12 hours groups, with 6 rats in each group. SAP rat model was prepared by injecting 5% sodium taurocholate via the retrograde cholangiopancreatic duct. Liver, kidney, lung, pancreas and serum samples were harvested after 3, 6 and 12 hours. In the Sham group, tissue and serum were harvested immediately after pancreas was turned over. The histopathological changes of the pancreas were observed microscopically by hematoxylin-eosin (HE) staining. The MIF levels of serum, liver, kidney, lung and pancreas were measured by enzyme linked immunosorbent assay (ELISA). (2) Clinical study: an observational study was conducted. Seventy-two adult patients within 24 hours of the onset of abdominal pain (blood amylase was 3 times the normal level), and the clinical diagnosis met the criteria of acute pancreatitis (AP) admitted to the emergency department of the First Affiliated Hospital of Zhengzhou University from December 2018 to October 2019 were enrolled. Venous blood was extracted and serum MIF level was determined by ELISA. Acute physiology and chronic health evaluation II (APACHE II) was recorded for 24 hours. Patients were divided into SAP group (17 cases), moderate severe acute pancreatitis (MSAP) group (25 cases), and mild acute pancreatitis (MAP) group (30 cases) according to the revised Atlanta criteria for comparison between groups. (1) The results of animal experiments showed that the serum, liver, and pancreatic MIF levels of rats in the SAP group all reached the peak at 6 hours after modeling, and the differences were statistically significant compared with the Sham group [serum MIF (ng/L): 2 862.79±238.33 vs. 1 728.32±197.59, liver MIF (ng/L): 2 141.39±328.07 vs. 1 372.70±163.41, pancreas MIF (ng/L): 4 468.00±1 324.31 vs. 1 572.06±108.40, all P < 0.01]; although the levels of MIF in serum, liver and pancreas decreased at 12 hours after modeling, they were still significantly higher than Sham group. However, there was no statistically significant difference in MIF levels of lung and kidney in SAP rats compared with Sham group at 3, 6 and 12 hours after molding. (2) Clinical observation showed that early serum MIF levels of SAP, MSAP and MAP patients decreased in order, (14.83±2.99), (10.17±2.64), and (7.21±2.47) μg/L, respectively; APACHE II scores also decreased in order, 10.41±3.74, 7.60±3.18 and 4.00±2.41 respectively. Correlation analysis showed that serum MIF levels in patients with SAP, MSAP, and MAP had a good correlation with APACHE II scores of the respective groups, showing that MIF levels was positively correlated with disease severity (SAP: r = 0.51, P = 0.03; MSAP: r = 0.45, P = 0.02; MAP: r = 0.45, P = 0.01). MIF can predict the occurrence of early SAP, and it is related to the severity of early AP.

MIF associated with pulmonary hypertension susceptibility and severity in non-dialysis Chronic kidney disease patients

Pulmonary hypertension (PAH) is one of the more serious complications of Chronic kidney disease (CKD), and its exact pathogenesis has not been clarified. As an upstream proinflammatory factor, macrophage migration inhibitor (MIF) is involved in the occurrence and development of many diseases. This study aimed to detect the relationship between serum MIF and PAH in non-dialysis CKD patients. A total of 382 non-dialysis CKD patients were enrolled in this study. Bio-Plex cytokine assay was used to detect MIF. CKD patients were divided into the PAH group and non-PAH group according to echocardiographic results. Relative risk was determined by logistic regression analysis. The pulmonary artery pressure in the CKD group was higher than that in the control group ( p &lt; 0.01). Pulmonary arterial pressure was higher in stage 4 to 5 CKD patients than in Stage 1 to 3 CKD patients ( p &lt; 0. 01), and the incidence of PAH was also increased ( p &lt; 0. 01). MIF in the CKD group were higher than in the control group ( p &lt; 0.05). MIF in CKD patients with PAH were higher than those without PAH ( p &lt; 0.05). Multivariate logistic regression analysis showed that MIF is correlated with PAH (OR = 10.745; 95% CI 2.288–89.447, p &lt; 0.05). PAH is common in non-dialysis CKD patients, and with the deterioration of kidney disease, the incidence of PAH is gradually increased, indicating that MIF plays an important role in the development of PAH in CKD patients.

Иммунопатогенные свойства SARS-CoV-2 как основа для выбора патогенетической терапии

Guinea-pigs were immunized via footpads with sheep red blood cells (SRBC) in saline. Histological examination of erythematous skin reaction was performed and effects of cyclophosphamide (CY) or BCG pre-treatment on the skin reaction were examined. Delayed-in-onset erythematous skin reaction accompanied by substantial basophil infiltration was elicited in guinea-pigs immunized with SRBC in saline. The erythema was augmented in size by CY which was injected 2 days before immunization. The reaction may be comparable to Jones-Mote type. In BCG pre-treated guinea-pigs, basophil infiltration at the skin reaction sites was reduced in number, but significant inhibition of macrophage migration was not detected in the presence of SRBC antigen. The reaction may be intermediate between Jones-Mote and the tuberculin type. Comparability of delayed skin reactions in guinea-pigs and delayed footpad reactions in mice or hamsters against SRBC is discussed.

Serum levels of macrophage migration inhibitory factor and interleukin 17 in patients with nonsegmental vitiligo

Introduction Immunological mechanisms definitely play a role in melanocyte loss in vitiligo. Several cytokines are involved in the regulation of immune cell stimulation and functional characterization. Interleukin 17 (IL-17) and macrophage migration inhibition factor (MIF) are among the cytokines reportedly involved in the pathogenesis of many other autoimmune diseases. Reports of upregulation of their serum level have been made in patients with vitiligo. Objective To evaluate the serum levels of MIF and IL-17 in patients with nonsegmental vitiligo and their relation to the occurrence and progression of the disease. Patients and methods This case–control study was conducted on 40 patients having nonsegmental vitiligo, of which 24 had active progression of the disease during the past 3 months, whereas the rest had a stable course over a year. Serum levels of IL-17 and MIF as determined by ELISA were compared among patients with those of 40 healthy controls. Their relations to disease severity (as determined by vitiligo area scoring index score), extent (as determined by body surface area of involvement), and activity were studied. Results Serum IL-17 and MIF were significantly higher in patients with vitiligo than in controls, with no significant difference between those with progressive or stable course. Both correlated positively with disease extent and severity in all patient groups. A highly significant positive correlation was found between serum IL-17 and MIF levels in all patient groups. Conclusion IL-17 and MIF contribute to vitiligo pathogenesis and could serve as indicators of disease extent and severity but not activity.

Glibenclamide ameliorates transplant-induced arteriosclerosis and inhibits macrophage migration and MCP-1 expression

AimsGlibenclamide, a diabetes mellitus type 2 medication, has anti-inflammatory and autoimmune properties. This study investigated the effects of glibenclamide on transplant-induced arteriosclerosis as well as the underlying molecular events. MethodsMale C57Bl/6 (H-2b) and BALB/c (H-2d) mice were used for aorta transplantation. We used hematoxylin and eosin (HE) and Elastic Van Gieson (EVG) staining for histological assessment, and qRT-PCR and ELISA to measure mRNA and protein levels. Mouse peritoneal macrophages were isolated for lipopolysaccharide (LPS) stimulation and glibenclamide treatment followed by ELISA, Western blot, and Transwell assays. ResultsGlibenclamide inhibited transplant-induced arteriosclerosis in vivo. Morphologically, glibenclamide reduced inflammatory cell accumulation and collagen deposition in the aortas. At the gene level, glibenclamide suppressed aortic cytokine mRNA levels, including interleukin-1β (IL-1β; 10.64 ± 3.19 vs. 23.77 ± 5.72; P < .05), tumor necrosis factor-α (TNF-α; 4.59 ± 0.78 vs. 13.89 ± 5.42; P < .05), and monocyte chemoattractant protein-1 (MCP-1; 202.66 ± 23.44 vs. 1172.73 ± 208.80; P < .01), while IL-1β, TNF-α, and MCP-1 levels were also reduced in the mouse sera two weeks after glibenclamide treatment (IL-1β, 39.40 ± 13.56 ng/ml vs. 78.96 ± 9.39 ng/ml; P < .01; TNF-α, 52.60 ± 13.00 ng/ml vs. 159.73 ± 6.76 ng/ml; P < .01; and MCP-1, 56.60 ± 9.07 ng/ml vs. 223.07 ± 36.28 ng/ml; P < .001). Furthermore, glibenclamide inhibited macrophage expression and secretion of inflammatory factors in vitro through suppressing activation of the nuclear factor-κB (NF-κB) pathway and MCP-1 production. ConclusionGlibenclamide protected against aorta transplantation-induced arteriosclerosis by reducing inflammatory factors in vivo and inhibited macrophage migration and MCP-1 production in vitro.

Myeloid HMG-CoA Reductase Determines Adipose Tissue Inflammation, Insulin Resistance, and Hepatic Steatosis in Diet-Induced Obese Mice.

Adipose tissue macrophages (ATMs) are involved in the development of insulin resistance in obesity. We have recently shown that myeloid cell-specific reduction of HMG-CoA reductase (Hmgcr m-/m- ), which is the rate-limiting enzyme in cholesterol biosynthesis, protects against atherosclerosis by inhibiting macrophage migration in mice. We hypothesized that ATMs are harder to accumulate in Hmgcr m-/m- mice than in control Hmgcr fl/fl mice in the setting of obesity. To test this hypothesis, we fed Hmgcr m-/m- and Hmgcr fl/fl mice a high-fat diet (HFD) for 24 weeks and compared plasma glucose metabolism as well as insulin signaling and histology between the two groups. Myeloid cell-specific reduction of Hmgcr improved glucose tolerance and insulin sensitivity without altering body weight in the HFD-induced obese mice. The improvement was due to a decrease in the number of ATMs. The ATMs were reduced by decreased recruitment of macrophages as a result of their impaired chemotactic activity. These changes were associated with decreased expression of proinflammatory cytokines in adipose tissues. Myeloid cell-specific reduction of Hmgcr also attenuated hepatic steatosis. In conclusion, reducing myeloid HMGCR may be a promising strategy to improve insulin resistance and hepatic steatosis in obesity.

Superiority of the Non-Glycosylated Form Over the Glycosylated Form of Irisin in the Attenuation of Adipocytic Meta-Inflammation: A Potential Factor in the Fight Against Insulin Resistance.

Irisin is an adipomyokine that promotes the browning of white adipose tissue and exhibits protective potential against the development of insulin resistance and type 2 diabetes. In our bodies, it occurs in its glycosylated form (G-IR): its activity is still poorly understood, because the majority of studies have used its non-glycosylated counterpart (nG-IR). Glycosylation can affect protein function: therefore, the present study attempted to compare the actions of both forms of irisin toward inflammatory activation of the main component of adipose tissue. The study was carried out in a coculture of 3T3 adipocytes and RAW 264.7 macrophages maintained in the presence of nG-IR or G-IR. The impact on vitality and the expression and release of key inflammatory mediators important for insulin resistance and diabetes development were assessed. The studies showed that both forms effectively inhibited the expression and release of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, macrophage chemotactic protein (MCP)-1, high-mobility group box (HMGB1), leptin, and adiponectin. However, in the case of TNF-α, IL-1β, MCP-1, and HMGB1, the inhibition exerted by nG-IR was more prominent than that by G-IR. In addition, only nG-IR significantly inhibited macrophage migration. Here, nG-IR seemed to be the stronger inhibitor of the development of obesity-related inflammation; however, G-IR also had anti-inflammatory potential.

Changes in the transcriptome profile of breast cancer cells grown as spheroids

BackgroundMulticellular tumor spheroids mimic the functional organization of tumors in vivo, providing biological readouts that predict the behavior of cancer cells more accurately. The current study aimed to evaluate the transcriptome (mRNAs and long non-coding RNAs) of multicellular tumor spheroids from breast cancer cells. MethodsMCF-7 cell spheroids were used; the transcriptome was analyzed using RNAseq and RNA microarrays; the secretion of macrophage migration inhibitor (MIF), a cytokine exported by the cholesterol efflux regulatory protein, was measured by ELISA. Linc00052 was inhibited using short-hairpin RNAs (shRNAs). ResultsWe found several differentially regulated mRNAs and lncRNAs in MCF-7 cell spheroids. We also found significant enrichment of the Wnt/B-catenin death receptor and the cholesterol metabolic processes. Interestingly, we also found an increased concentration of MIF. Further, at 12 and 20 days of 3D culture we found 221 and 1146 dysregulated lncRNAs, respectively; including linc00052 (long intergenic non-protein coding RNA 52), which has been involved in breast cancer. Linc00052 knock-down experiments suggest that it could be a key regulator of cholesterol pathways in breast cancer. ConclusionsOur data shows that tumor spheroids can induce changes in the transcriptome of the cultured cells, including both mRNAs and ncRNA. One of the major changes included the deregulation of cholesterol pathways, of which linc00052 is apparently a key regulator.

Role of Ox-LDL and LOX-1 in Atherogenesis.

Oxidized LDL (ox-LDL) plays a central role in atherosclerosis by acting on multiple cells such as endothelial cells, macrophages, platelets, fibroblasts and smooth muscle cells through LOX-1. LOX-1 is a 50 kDa transmembrane glycoprotein that serves as receptor for ox-LDL, modified lipoproteins, activated platelets and advance glycation end-products. Ox- LDL through LOX-1, in endothelial cells, causes increase in leukocyte adhesion molecules, activates pathways of apoptosis, increases reactive oxygen species and cause endothelial dysfunction. In vascular smooth muscle cells and fibroblasts, they stimulate proliferation, migration and collagen synthesis. LOX-1 expressed on macrophages inhibit macrophage migration and stimulate foam cell formation. They also stimulate generation of metalloproteinases and contribute to plaque instability and thrombosis. Drugs that modulate LOX-1 are desirable targets against atherosclerosis. Many naturally occurring compounds have been shown to modulate LOX-1 expression and atherosclerosis. Currently, novel drug design techniques are used to identify molecules that can bind to LOX-1 and inhibit its activation by ox-LDL. In addition, techniques using RNA interference and monoclonal antibody against LOX-1 are currently being investigated for clinical use.

Association between plasma macrophage migration inhibitor factor and deep vein thrombosis in patients with spinal cord injuries.

The patients with spinal cord injury (SCI) suffered significantly higher risk of deep vein thrombosis (DVT) than normal population. The aim was to assess the clinical significance of macrophage migration inhibitory factor (MIF) as the risk factor for DVT in acute SCI patients. 207 Chinese patients were enrolled in this study, including thirty-nine (39) patients (18.8 %; 95 %CI: 13.5 %–24.2 %) diagnosed as DVT at the follow-up of 1 month. Nine (9) of the 39 patients (23.1%) were suspected of thrombosis before the screening. The MIF levels in plasma of DVT patients were significantly higher than DVT-free patients. The risks of DVT would be increased by 11 % (OR unadjusted: 1.11; 95% CI, 1.06–1.17, P<0.001) and 8 % (OR adjusted: 1.08; 1.03–1.14, P=0.001), for each additional 1 ng/ml of MIF level. Furthermore, after MIF was combined with established risk factors, area under the receiver operating characteristic curve (standard error) was increased from 0.82(0.035) to 0.85(0.030). The results showed the potential association between the high MIF levels in plasma and elevated DVT risk in SCI patients, which may assist on early intervention.

Cell Permeable NBD Peptide-Modified Liposomes by Hyaluronic Acid Coating for the Synergistic Targeted Therapy of Metastatic Inflammatory Breast Cancer.

Chronic inflammation is closely related to the development, deterioration, and metastasis of tumors. Recently, many studies have shown that down-regulating the expression of inflammation by blocking nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways could significantly inhibit tumor growth and metastasis. The combined application of curcumin (CUR) and celecoxib (CXB) has been proven to exert a synergistic antitumor effect via inhibiting the activation of NF-κB and STAT3. TAT-NBD (TN) peptide, a fusion peptide of NF-κB essential modulator (NEMO)-binding domain peptide (NBD) and cell-penetrating peptide (TAT), can selectively block NF-κB activating pathway resulting in tumor growth inhibition. In the present study, a novel TN-modified liposome coloading both CXB and CUR (TN-CCLP) at a synergistic ratio was first constructed with the property of synchronous release, then hyaluronic acid (HA) as CD44 targeting moiety was coated on the surface of the cationic liposome via electrostatic interaction to prepare the anionic HA/TN-CCLP. In vitro results of cytotoxicity, macrophage migration inhibition, and anti-inflammation efficacy revealed that TN-CCLP and HA/TN-CCLP were significantly superior to TN-LP and CCLP, while TN-CCLP exhibited better effects than HA/TN-CCLP due to higher cellular uptake ability. Different from in vitro data, after systematically treating 4T1 breast tumor-bearing mice, HA/TN-CCLP exerted the most striking effects on anti-inflammation, inhibition of macrophage recruitment, and antitumor because of the longest circulation time and maximum tumor accumulation. In particular, HA/TN-CCLP could availably block the lung metastasis of breast cancer. Taken together, the novel CD44 targeted TN-CCLP exhibited the potential for inhibiting tumor development and metastasis through improving inflammatory infiltration of tumor tissue.

Macrophage Migration Inhibitor Promoted the Intrahepatic Bile Duct Injury in Rats with Severe Acute Pancreatitis.

Macrophage migration inhibitory factor (MIF) is involved in many acute and chronic inflammatory diseases. However, its role in intrahepatic bile duct (IBD) cell damage associated with severe acute pancreatitis (SAP) remains unclear. This study was aimed to identify the role of MIF and its underlying mechanisms in SAP complicated by IBD cell damage. Forty-eight specific-pathogen-free male Wistar rats were randomly divided into four groups (N = 12): a sham operation group (SO group) and three SAP model groups (SAP-3h, SAP-6h, and SAP-12h). Immunohistochemistry was used to detect the expression of MIF and P38 in IBD cells. MIF mRNA expression in IBD cells was observed using real-time fluorescent quantitative polymerase chain reaction (real-time PCR). In addition, Western blotting was performed to detect the protein expression of P38, phosphorylated P38 (P-P38), nuclear factor-κB (NF-κB p65), and tumor necrosis factor alpha (TNF-α). Enzyme-linked immunosorbent assays were used to analyze the levels of TNF-α, IL-1β, and IL-6 in the IBD of rats. Compared with the SO group, the expression of MIF in the IBD was significantly upregulated both at mRNA and at protein levels in the SAP group. Besides, the protein expression levels of P38, P-P38, NF-κB, p65, TNF-α, IL-1β, and IL-6 in the IBD in rats were also significantly increased in the SAP group and the levels increased gradually as acute pancreatitis progressed (all P < 0.05). MIF may promote the IBD injury and inflammatory reaction in SAP via activating the P38-MAPK and NF-κB signaling pathways.

Antiemetic doses of dexamethasone and their effects on immune cell populations and plasma mediators of inflammation resolution in healthy volunteers

IntroductionThe synthetic glucocorticoid dexamethasone is a commonly administered antiemetic. It has immunosuppressive effects and may alter postoperative blood glucose concentrations. Dexamethasone can effect key enzymes involved in inflammation resolution that is an active process driven by specialised lipid mediators of inflammation resolution (SPM). The purpose of this study in healthy volunteers was to examine whether dexamethasone effects cell populations and synthesis of SPM that are critical for the resolution of inflammation. MethodsThirty-two healthy volunteers were randomly allocated to receive saline (Control) or dexamethasone 2 mg, 4 mg or 8 mg intravenously. Venous blood samples were collected at baseline before administration of treatment, and at 4 h, 24 h and one-week post-treatment. At each time point, measurements included blood glucose and macrophage migration inhibition factor (MMIF), full blood count including lymphocyte subsets, monocytes, neutrophils, eosinophils and basophils by flow cytometry, and plasma SPM using liquid chromatography tandem mass spectrometry. The effect of dexamethasone dose and time on all measures was analysed using linear mixed models. ResultsThere was a dose-dependent increase in neutrophil count after dexamethasone that persisted for 24 h. In contrast, there was a dose-dependent reduction in counts of monocytes, lymphocytes, basophils and eosinophils 4 h after dexamethasone, followed by a rebound increase in cell counts at 24 h. Seven days after administration of dexamethasone, all cell counts were similar to baseline levels. MMIF concentration, glucose and natural killer cell counts were not significantly affected by dexamethasone. There was a significant gender effect on plasma SPM such that levels of 17-HDHA, RvD1, 17R-RvD1 and RvE2 in females were on average 14%–50% lower than males. In a linear mixed model that adjusted for neutrophil count, there was a significant interaction between the dose of dexamethasone and time, on plasma 17R-RvD1 such that plasma 17R-RvD1 fell in a dose-dependent manner until 4 h after administration of dexamethasone. There were no significant effects of dexamethasone on the other plasma SPM (18-HEPE, RvE2, 17-HDHA, RvD1, RvD2 and 14-HDHA) measured. DiscussionThis is the first study in healthy volunteers to demonstrate that commonly employed antiemetic doses of dexamethasone affect immune cell populations and plasma levels of 17R-RvD1 an SPM with anti-nociceptive properties. If similar changes occur in surgical patients, then this may have implications for acute infection risk in the post-operative period.

Fibroblast growth factor 21 regulates foam cells formation and inflammatory response in Ox-LDL-induced THP-1 macrophages.

Macrophages are paramount to the initiation and procession of atherosclerosis, thus targeting macrophages in the progress of atherosclerosis is indispensable. Therefore, we perform in vitro experiments to investigate the effects of FGF-21 on macrophages in the progress of atherosclerosis. First, we use phorbol-12-myristate-13-acetate (PMA), a phorbol ester, to induce THP-1 cells into macrophages as macrophages model. After that we use Ox-LDL to induce macrophages into foam cells and simultaneously administrate with FGF-21 or not to determine whether FGF-21 has effects on foam cells formation and related inflammatory response. Wound healing results show that FGF-21 can inhibit macrophage migration. Oil Red-O stain, immunofluorescence and flow cytometer results show that FGF-21 can repress cholesterol accumulation in macrophages thereby inhibit foam cells formation and these effects can be abolished by FGFR inhibitor. Moreover, real-time PCR results showed that FGF-21 significantly reduces expression of inflammatory factors including IL-1α, IL-6 and TNF-α and this effect can be abolished by FGFR inhibitor. Furthermore, to determine the mechanism of FGF-21 regulates inflammatory response in Ox-LDL-induced THP-1 macrophages, western blotting results show that after treatment of Ox-LDL in macrophages, NF-κB signaling pathway is activated but FGF-21 can significantly inhibit this pathway. In addition, FGF-21 also regulates some regulators of lipid metabolism after treatment of Ox-LDL in macrophages. Above all, our findings demonstrate that FGF-21 can regulate foam cells formation, macrophage migration, inflammatory response and lipid metabolism in Ox-LDL-induced THP-1 macrophages.

The role of UNC5b in ox-LDL inhibiting migration of RAW264.7 macrophages and the involvement of CCR7

The formation of macrophage foam cells by ingesting ox-LDL and focal retention in the subendothelial space are the hallmarks of the early atherosclerotic lesion. The C-C chemokine receptor type 7 (CCR7) is positively correlated with the macrophage migration. But the mechanism of CCR7 regulation is not fully clearness. In the present study, we demonstrates that expression in UNC5b and netrin-1 was enhanced in respond to ox-LDL in Raw264.7 macrophage and associated with decreasing cell migration. Interestingly, it was found that ox-LDL significantly downregulate CCR7 gene expression. The expression of CCR7 in mRNA and protein levels were decreased in ox-LDL treated Raw264.7 macrophage when we over expression of UNC5b with pcDNA3.1-UNC5b plasmid. We got the inverse results after silence UNC5b gene with siUNC5b. Meanwhile, the data show that in ox-LDL inducement, UNC5b down-regulated CCR7, and then inhibited macrophage migration. This novel phenomenon is of a crucial highlights to understand deeply the pathogenesis of atherosclerosis. The molecular mechanism of CCR7 regulation deserves intensive study.

Overexpression of macrophage migration inhibitory factor and functionally-related genes, D-DT, CD74, CD44, CXCR2 and CXCR4, in glioblastoma.

The macrophage migration inhibition factor (MIF) is a cytokine with multiple biological functions, including the cancer-associated processes, cell cycle deregulation, angiogenesis and metastatization. The present study investigated the expression of MIF and its functionally associated genes (D-DT, CD74, CD44, CXCR2 and CXCR4) in glioblastoma multiforme (GBM). The data were obtained from The Cancer Genome Atlas databank, through the cBioportal web-based utility (cbioportal.org/). A significant increase was observed in the majority of these genes in GBM samples compared with lower grade gliomas, however no significant correlation among the selected genes and the overall survival of the patients was identified. In contrast, the expression of MIF exhibited a trend toward an increase in overall survival and a significant increase of MIF expression was observed in samples of patients who underwent neoadjuvant treatment. In conclusion these data indicate that MIF and its receptors are involved in GBM progression and maintenance. Deciphering the precise biological significance in GBM would favor the adoption of tailored approaches to modulate the function of MIF and its associated genes for the treatment of the disease.

Microbiota metabolites derived from tryptophan modulate macrophage inflammation and migration through AMP-activated protein kinase

Abstract It is established that the gut microbiota plays an important role in Non-Alcoholic Fatty Liver Disease (NAFLD) and different bacterial taxa have been correlated to disease. However, the specific metabolites through which the microbiota exert their effects and the target pathways in host cells are not fully understood. We used liquid chromatography-mass spectrometry metabolomics to identify two tryptophan-derived metabolites – tryptamine (TA) and indole-3-acetate (I3A) – that require the microbiota and are depleted in high-fat diet mice compared to low fat diet mice. Both I3A and TA reduced palmitate and LPS induced production of pro-inflammatory cytokines (TNFα, IL-1β and MCP-1) in RAW 264.7 macrophages, as well as inhibited macrophage migration toward the chemokine MCP-1. We identified that both palmitate and LPS reduced levels of p-AMPK and the addition of I3A and TA reversed p-AMPK reduction. Since the p-AMPK activator AICAR reduced palmitate and LPS induced inflammatory cytokine production, we propose that I3A and TA modulate inflammation through modulating p-AMPK levels.

Elevated plasma macrophage migration inhibitor factor as a risk factor for the development of post-stroke depression in ischemic stroke

BackgroundMacrophage migration inhibitory factor (MIF), a central cytokine of the innate immunity and inflammatory responses, has been reported to link to the pathophysiology of cardiovascular disease and depression. The aim of this study was to test the possible association between plasma MIF and the development of post-stroke depression (PSD) in Chinese patients with acute ischemic stroke (AIS). MethodsThe first-ever AIS patients who were hospitalized at Affiliated Hospital of Weifang Medical College during the period from November 2015 to September 2017 were included. Neurological and neuropsychological evaluations were conducted at the 3-month follow-up. Plasma concentrations of MIF were tested by Quantikine Human MIF Immunoassay. Plasma levels of homocysteine (HCY), C-reactive protein (CRP) and Interleukin 6 (IL-6) were also tested. Results were expressed as percentages for categorical variables and as medians (Interquartile range-IQR) for the continuous variables. ResultsFinally, 333 stroke patients were included, and 95 out of those patients (28.5%) were classified as major depression. In the patients with major depression, plasma levels of MIF were higher compared with those in patients free-depression [27.3(IQR, 23.5–34.9) ng/ml vs. 20.9(IQR, 17.0–24.8) ng/ml; Z = 8.369, P < 0.001]. For each 1unit increase of MIF, the unadjusted and adjusted risk of PSD increased by 18% (odds ratios [OR]: 1.18; 95% confidence interval [CI], 1.13–1.23, P < 0.001) and 11% (1.11; 1.02–1.16, P = 0.001), respectively. In a multivariate model using the elevated levels of MIF (≥median) vs. normal (<median) together with the other significant clinical variables, the marker displayed prognostic information (PSD: OR for fourth quartile, 3.05 [95% CI, 1.65–6.11; P < 0.001]). When MIF was added to the model containing established significant risk factors, Area Under the Receiver Operating Characteristic curve (AUROC; standard error) was increased from 0.81(0.025) to 0.86(0.019). A significant difference in the AUROC between the established risk factors alone and the addition of MIF was observed (difference, 0.05[0.006]; P = 0.004). ConclusionThe present study demonstrated that elevated plasma levels of MIF at admission were associated with increased risk of PSD in the next three months and might be useful in identifying stroke at risk for PSD for early prevention strategies.

Anti-inflammatory effect of diterpenes-enriched fractions from Pterodon polygalaeflorus through inhibition of macrophage migration and cytokine production.

To evaluate the anti-inflammatory potential of Pterodon polygalaeflorus hexane extract (HE) and its fractions on macrophage migration in vitro and in vivo. Hexane extract from P. polygalaeflorus fruits was fractionated and yielded four fractions. RAW 264.7 cells were treated with samples to evaluate cell viability (MTT assay), cell migration (wound healing and transwell assays), CD14 expression (flow cytometry), iNOS and cytokine mRNA expression (RT-qPCR), NO (Griess reaction) and cytokine (ELISA) production. In vivo migration was evaluated on the thioglycollate-induced peritonitis model. Qualitative analysis was performed by GC-MS. All fractions inhibited the NO production by LPS-stimulated RAW 264.7 cells. Fr3 and Fr4 presented the lowest IC50 values. The expressions of iNOS and IL-1β, TNF-α and IL-10 cytokines were inhibited by Fr3 and Fr4, whereas the CD14 expression was only inhibited by Fr3. All the samples inhibited RAW 264.7 migration in the wound healing and transwell assays. Fr3 and Fr4 reduced the migration of Mac-1+ Gr-1- cells to the peritoneum and presented in their compositions: 6α-hydroxy-7β-acetoxyvouacapan-17β-oate, methyl 6α,7β-dihydroxyvouacapan-17β-oate, methyl 6α-acetoxy-7β-hydroxyvouacapan-17β-oate, geranylgeraniol and 14,15-epoxy-geranylgeraniol. The anti-inflammatory effects of Fr3 and Fr4 involve inhibition of cell migration, iNOS expression and NO production, cytokine expression (mRNA and proteins) and CD14 expression (Fr3).

CXCL1-CXCR2 axis mediates angiotensin II-induced cardiac hypertrophy and remodelling through regulation of monocyte infiltration.

Chemokine-mediated monocyte infiltration into the damaged heart represents an initial step in inflammation during cardiac remodelling. Our recent study demonstrates a central role for chemokine receptor CXCR2 in monocyte recruitment and hypertension; however, the role of chemokine CXCL1 and its receptor CXCR2 in angiotensin II (Ang II)-induced cardiac remodelling remain unknown. Angiotensin II (1000 ngkg-1min-1) was administrated to wild-type (WT) mice treated with CXCL1 neutralizing antibody or CXCR2 inhibitor SB265610, knockout (CXCR2 KO) or bone marrow (BM) reconstituted chimeric mice for 14 days. Microarray revealed that CXCL1 was the most highly upregulated chemokine in the WT heart at Day 1 after Ang II infusion. The CXCR2 expression and the CXCR2+ immune cells were time-dependently increased in Ang II-infused hearts. Moreover, administration of CXCL1 neutralizing antibody markedly prevented Ang II-induced hypertension, cardiac dysfunction, hypertrophy, fibrosis, and macrophage accumulation compared with Immunoglobulin G (IgG) control. Furthermore, Ang II-induced cardiac remodelling and inflammatory response were also significantly attenuated in CXCR2 KO mice and in WT mice treated with SB265610 or transplanted with CXCR2-deficienct BM cells. Co-culture experiments in vitro further confirmed that CXCR2 deficiency inhibited macrophage migration and activation, and attenuated Ang II-induced cardiomyocyte hypertrophy and fibroblast differentiation through multiple signalling pathways. Notably, circulating CXCL1 level and CXCR2+ monocytes were higher in patients with heart failure compared with normotensive individuals. Angiotensin II-induced infiltration of monocytes in the heart is largely mediated by CXCL1-CXCR2 signalling which initiates and aggravates cardiac remodelling. Inhibition of CXCL1 and/or CXCR2 may represent new therapeutic targets for treating hypertensive heart diseases.