- The cGAS/STING Pathway Is Important for Dendritic Cell Activation but Is Not Essential to Induce Protective Immunity against Mycobacterium tuberculosis Infection. [Journal Article]
- JIJ Innate Immun 2018 May 23; :1-14
- Mycobacterium tuberculosis (Mtb) infection remains a major public health concern. The STING (stimulator of interferon genes) pathway contributes to the cytosolic surveillance of host cells. Most stud...
Mycobacterium tuberculosis (Mtb) infection remains a major public health concern. The STING (stimulator of interferon genes) pathway contributes to the cytosolic surveillance of host cells. Most studies on the role of STING activation in Mtb infection have focused on macrophages. Moreover, a detailed investigation of the role of STING during Mtb infection in vivo is required. Here, we deciphered the involvement of STING in the activation of dendritic cells (DCs) and the host response to Mtb infection in vivo. In DCs, this adaptor molecule was important for Ifn-β expression and IL-12 production as well as for the surface expression of the activation markers CD40 and CD86. We also documented that Mtb DNA induces STING activation in murine fibroblasts. In vivo Mtb aerogenic infection induced the upregulation of the STING and cGAS (cyclic GMP-AMP synthase) genes, and Ifn-β pulmonary expression was dependent on both sensors. However, mice deficient for STING or cGAS presented a similar outcome to wild-type controls, with no major alterations in body weight gain, bacterial burden, or survival. Lung inflammation, proinflammatory cytokine production, and inflammatory cell recruitment were similar in STING- and cGAS-deficient mice compared to wild-type controls. In summary, although the STING pathway seems to be crucial for DC activation during Mtb infection, it is dispensable for host protection in vivo.
- A Central Role for Heme Oxygenase-1 in the Control of Intestinal Epithelial Chemokine Expression. [Journal Article]
- JIJ Innate Immun 2018 May 23; :1-11
- In mucosal inflammatory disorders, the protective influence of heme oxygenase-1 (HO-1) and its metabolic byproducts, carbon monoxide (CO) and biliverdin, is a topic of significant interest. Mechanism...
In mucosal inflammatory disorders, the protective influence of heme oxygenase-1 (HO-1) and its metabolic byproducts, carbon monoxide (CO) and biliverdin, is a topic of significant interest. Mechanisms under investigation include the regulation of macrophage function and mucosal cytokine expression. While there is an increasing recognition of the importance of epithelial-derived factors in the maintenance of intestinal mucosal homeostasis, the contribution of intestinal epithelial cell (IEC) HO-1 on inflammatory responses has not previously been investigated. We examined the influence of modulating HO-1 expression on the inflammatory response of human IECs. Engineered deficiency of HO-1 in Caco-2 and T84 IECs led to increased proinflammatory chemokine expression in response to pathogenic bacteria and inflammatory cytokine stimulation. Crosstalk with activated leukocytes also led to increased chemokine expression in HO-1-deficient cells in an IL-1β dependent manner. Treatment of Caco-2 cells with a pharmacological inducer of HO-1 led to the inhibition of chemokine expression. Mechanistic studies suggest that HO-1 and HO-1-related transcription factors, but not HO-1 metabolic products, are partly responsible for the influence of HO-1 on chemokine expression. In conclusion, our data identify HO-1 as a central regulator of IEC chemokine expression that may contribute to homeo-stasis in the intestinal mucosa.
- Extraction and characterization of cashew tree (Anacardium occidentale) gum; use in aceclofenac dental pastes. [Journal Article]
- IJInt J Biol Macromol 2018 May 20
- In the current work, the usefulness of extracted cashew tree gum (CG) as pharmaceutical excipient in dental pastes containing AC (for the pain management in the periodontitis) was investigated. CG wa...
In the current work, the usefulness of extracted cashew tree gum (CG) as pharmaceutical excipient in dental pastes containing AC (for the pain management in the periodontitis) was investigated. CG was extracted from crude exudate of cashew tree (Anacardium occidentale, family: Anacardiaceae) (yield 19.22%). Physicochemical characteristics like colour, odour, taste, solubility, pH and viscosity of extracted CG were estimated; the phytochemical identification tests indicated the presence of carbohydrates and mucilage within it. It was also characterized by FTIR spectroscopy and 1H NMR analyses. Using the extracted CG (as natural mucoadhesive polymer) with calcium carbonate (abrasive agent), glycerin (humectant and cosolvent), methyl paraben (preservative), sodium lauryl sulfate (surfactant) and camphor (flavoring agent), 1% w/w AC dental pastes was formulated via conventional trituration. The drug contents, viscosities and pHs, tube extrudabilities and tube spreadabilities of these dental pastes were observed within permissible ranges. The dental pastes demonstrated sustained AC releasing over 6 h, in vitro and also revealed good adhesion to the oral mucosal membrane. These 1% w/w AC dental pastes can be used in the effectual management of dental inflammation and pain through local delivery of AC over a prolonged in the periodontitis treatment.
- Ontogeny of white matter, toll-like receptor expression, and motor skills in the neonatal ferret. [Journal Article]
- IJInt J Dev Neurosci 2018 May 20
- Inflammation caused by perinatal infection, superimposed with hypoxia and/or hyperoxia, appears to be important in the pathogenesis of preterm neonatal encephalopathy, with white matter particularly ...
Inflammation caused by perinatal infection, superimposed with hypoxia and/or hyperoxia, appears to be important in the pathogenesis of preterm neonatal encephalopathy, with white matter particularly vulnerable during the third trimester. The associated inflammatory response is at least partly mediated through Toll-like receptor (TLR)-dependent mechanisms. Immunohistochemistry, gene expression, and behavioral studies were used to characterize white matter development and determine TLR3 and TLR4 expression and accumulation in the neonatal ferret brain. Expression of markers of white matter development increased significantly between postnatal day (P)1 and P10 (NG2, PDGFRα) or P15 (Olig2), and either remained elevated (NG2), or decreased again at P40 (PDGFRα, Olig2). Olig2 immunostaining within the internal capsule was also greatest at P15. Myelin basic protein (MBP) immunostaining and mRNA expression increased markedly from P15 to P40 and into adulthood, which correlated with increasing performance on behavioral tests (negative geotaxis, cliff aversion, righting reflex, and catwalk gait analysis). TLR4 and TLR3 positive staining was low at all ages, but TLR3 and TLR4 mRNA expression both increased significantly from P1 to P40. Following lipopolysaccharide (LPS) and hypoxia/hyperoxia exposure at P10, meningeal and parenchymal inflammation was seen, including an increase in TLR4 positive cells. These data suggest that the neuroinflammation associated with prematurity could be modeled in the newborn ferret.
- Neutrophils Provide a Favorable IL-1-Mediated Immunometabolic Niche that Primes GLUT4 Translocation and Performance in Skeletal Muscles. [Journal Article]
- CRCell Rep 2018 May 22; 23(8):2354-2364
- Metabolic immunomodulation involving IL-1 has been investigated for unfavorable metabolic effects, including obesity, but a potentially favorable role for IL-1 remains unclear. Here, we find mechanis...
Metabolic immunomodulation involving IL-1 has been investigated for unfavorable metabolic effects, including obesity, but a potentially favorable role for IL-1 remains unclear. Here, we find mechanistic interactions between working skeletal muscles and locally recruited neutrophils expressing IL-1β, which supports muscle performance through priming exercise-dependent GLUT4 translocation. Thus, during exercise, both IL-1α/β-deficient and neutrophil-depleted mice similarly exhibit increased fatigability associated with impaired muscle glucose homeostasis due to GLUT4 dysregulation. Deficiency of IL-1-producing neutrophils results in intrinsic abnormalities represented by aberrant Rac1 signaling and irregular GLUT4-storage vesicles, suggesting that these properties are maintained by local IL-1 produced by recruited neutrophils upon exercise, possibly on a daily basis. We propose that neutrophils are highly engaged in skeletal muscle performance via IL-1 regulation, which coordinates favorable inflammatory microenvironments supporting muscle glucose metabolism.
- Myosin IIa Promotes Antibody Responses by Regulating B Cell Activation, Acquisition of Antigen, and Proliferation. [Journal Article]
- CRCell Rep 2018 May 22; 23(8):2342-2353
- B cell responses are regulated by antigen acquisition, processing, and presentation to helper T cells. These functions are thought to depend on contractile activity of non-muscle myosin IIa. Here, we...
B cell responses are regulated by antigen acquisition, processing, and presentation to helper T cells. These functions are thought to depend on contractile activity of non-muscle myosin IIa. Here, we show that B cell-specific deletion of the myosin IIa heavy chain reduced the numbers of bone marrow B cell precursors and splenic marginal zone, peritoneal B1b, and germinal center B cells. In addition, myosin IIa-deficient follicular B cells acquired an activated phenotype and were less efficient in chemokinesis and extraction of membrane-presented antigens. Moreover, myosin IIa was indispensable for cytokinesis. Consequently, mice with myosin IIa-deficient B cells harbored reduced serum immunoglobulin levels and did not mount robust antibody responses when immunized. Altogether, these data indicate that myosin IIa is a negative regulator of B cell activation but a positive regulator of antigen acquisition from antigen-presenting cells and that myosin IIa is essential for B cell development, proliferation, and antibody responses.
- Modulating macrophage polarization through CCR2 inhibition and multivalent engagement. [Journal Article]
- MPMol Pharm 2018 May 23
- Excessive or prolonged recruitment of inflammatory monocytes to damaged tissue can significantly worsen patient outcomes. Monocytes migrate to sites of tissue inflammation in response to high local c...
Excessive or prolonged recruitment of inflammatory monocytes to damaged tissue can significantly worsen patient outcomes. Monocytes migrate to sites of tissue inflammation in response to high local concentrations of CCL2, a chemokine that binds to and signals through the CCR2 receptor. While the role of CCR2 in cellular migration is well studied, it is unclear how CCR2 inhibition affects macrophage polarization and if multivalency can increase downstream signaling effects. Using affinity selection with a phage library, we identified a novel scFv (58C) that binds specifically and with high affinity to the N-terminal domain of CCR2 (KD = 59.8 nM). The newly identified 58C-scFv bound to native CCR2 expressed on macrophages and MDA-MB-231 cells, inhibited migration, and induced a pro-inflammatory M1-phenotype in macrophages. The M1/M2 macrophage phenotype ratio for monomeric 58C-scFv was significantly increased over the negative control by 1.0x104-fold (iNOS/Arg-1), 5.1x104-fold (iNOS/Mgl2), 3.4x105-fold (IL-6/Arg-1), and 1.7x106-fold (IL-6/Mgl2). Multivalent display of 58C-scFv on liposomes further reduced migration of both cell types by 25 to 40% and enhanced M1 polarization by 200% over monomeric 58C-scFv. These studies demonstrate that CCR2 inhibition polarizes macrophages towards an inflammatory M1 phenotype and that multivalent engagement of CCR2 increases the effects of 58C-scFv on polarization and migration. These data provide important insights into the role of multivalency in modulating binding, downstream signaling, and cellular fate.
- Vaccine immunotherapy with ARNAX induces tumor-specific memory T cells and durable anti-tumor immunity in mouse models. [Journal Article]
- CSCancer Sci 2018 May 23
- Immunological checkpoint blockade therapies benefit a limited population of cancer patients. We have previously shown that vaccine immunotherapy with TLR3-adjuvant and tumor antigen overcomes anti-pr...
Immunological checkpoint blockade therapies benefit a limited population of cancer patients. We have previously shown that vaccine immunotherapy with TLR3-adjuvant and tumor antigen overcomes anti-programmed death ligand-1 (PD-L1) resistance in mouse tumor models. In this study, four different OVA-expressing tumor cell lines were implanted into syngeneic mice and subjected to antitumor immunotherapy using ARNAX and whole OVA protein. ARNAX is a Toll-like receptor 3-specific agonist that does not activate the MAVS pathway, and thus does not induce systemic inflammation. Dendritic cell priming and proliferative cytotoxic T lymphocytes (CTLs) were induced by ARNAX + OVA, but complete remission was achieved only in PD-L1-low cell line of EG7. Addition of anti-PD-L1 antibody to the ARNAX+OVA therapy brought complete remission to another PD-L1-high subline of EG7. Tumor shrinkage but not remission was observed in MO5 in that recipe. We analyzed tumor cells and tumor-infiltrating immune cells to identify factors associated with successful ARNAX vaccine therapy. Tumors that responded to ARNAX therapy expressed high levels of major histocompatibility complex class I and low levels of PD-L1. The tumor-infiltrating immune cells in ARNAX-susceptible tumors contained lesser immunosuppressive myeloid cells with low PD-L1 expression. The combination with anti-PD-L1 antibody functioned not only within tumor sites but also lymphoid tissues, augmenting the therapeutic efficacy of the ARNAX vaccine. Notably, ARNAX therapy induced memory CD8+ T cells and the rejection of re-implanted tumors. Thus, ARNAX vaccine + anti-PD-L1 therapy enabled permanent remission against some tumors that stably present antigens.
- Synergy between peroxisome proliferator-activated receptor γ agonist and radiotherapy in cancer. [Journal Article]
- CSCancer Sci 2018 May 23
- ANGIOGENESIS AND INFLAMMATION ARE CRUCIAL PROCESSES, THROUGH WHICH THE: tumor microenvironment (TME) influences tumor progression. In this STUDY, WE REVEALED THAT PEROXISOME PROLIFERATOR-ACTIVATED RE...
ANGIOGENESIS AND INFLAMMATION ARE CRUCIAL PROCESSES, THROUGH WHICH THE: tumor microenvironment (TME) influences tumor progression. In this STUDY, WE REVEALED THAT PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR Γ (PPARΓ) IS: NOT ONLY EXPRESSED IN CT26 AND 4T1 TUMOR CELL LINES BUT ALSO IN CELLS OF TME,: including endothelial cells and tumor-associated macrophages (TAMs). In addition, WE DEMONSTRATED THAT ROSIGLITAZONE MAY INDUCE TUMOR VESSEL NORMALIZATION AND REDUCE: TAM infiltration. Additionally, 4T1 and CT26 tumor-bearing mice treated with ROSIGLITAZONE IN COMBINATION WITH RADIOTHERAPY DISPLAYED A SIGNIFICANT REDUCTION IN: lesion size and lung metastasis. We reported that a single dose of 12 Gy irradiation strongly inhibits local tumor angiogenesis. The secretion of the chemokine CCL2 in RESPONSE TO LOCAL IRRADIATION FACILITATES THE RECRUITMENT OF MIGRATING CD11B+: MYELOID MONOCYTES AND TAMS TO IRRADIATED SITES THAT INITIATE VASCULOGENESIS AND: enable tumor recurrence after radiotherapy. We found that rosiglitazone partially DECREASES CCL2 SECRETION BY TUMOR CELLS AND REDUCES THE INFILTRATION OF CD11B+: MYELOID MONOCYTES AND TAMS TO IRRADIATED TUMORS, THEREBY DELAYING TUMOR: regrowth after radiotherapy. Therefore, the combination of the PPARγ agonist ROSIGLITAZONE WITH RADIOTHERAPY ENHANCES THE EFFECTIVENESS OF RADIOTHERAPY TO IMPROVE: local tumor control, decrease distant metastasis risks and delay tumor recurrence. This article is protected by copyright. All rights reserved.
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- Graves' ophthalmopathy: low-dose dexamethasone reduces retinoic acid receptor-alpha gene expression in orbital fibroblasts. [Journal Article]
- AEArch Endocrinol Metab 2018 May 17
- CONCLUSIONS: Orbital fibroblasts from a GO patient expressed the RARα gene, which was unaffected by higher, but decreased with lower doses of glucocorticoid.