Rehman, R. | Search bioRxiv

bioRxiv2020

Selective Nanotherapeutic Targeting of the Neutrophil Subset Mediating Inflammatory Injury

Inflammatory tissue injury such as acute lung injury (ALI) is a disorder that leads to respiratory failure, a major cause of morbidity and mortality worldwide. Excessive neutrophil influx is a critical pathogenic factor in the development of ALI. Here, we identify the subset of neutrophils that is responsible for ALI and lethality in polymicrobial sepsis. The pro-inflammatory neutrophil subpopulation was characterized by its unique ability to endocytose albumin nanoparticles (ANP), upregulation of pro-inflammatory cytokines and chemokines as well as the excessive production of reactive oxygen species (ROS) in models of endotoxemia and septicemia. ANP delivery of the drug piceatannol, a spleen tyrosine kinase (Syk) inhibitor, to the susceptible subset of neutrophils, prevented ALI and mortality in mice subjected to polymicrobial infection. Targeted inhibition of Syk in ANP-susceptible neutrophils had no detrimental effect on neutrophil-dependent host defense because the subset of ANPlow neutrophils effectively controlled polymicrobial infection. The results show that neutrophil heterogeneity can be leveraged therapeutically to prevent ALI without compromising host defense.Competing Interest StatementABM, AS, KB have interests in the biotechnology company Nano Biotherapeutics Inc.View Full Text

immunology↗

bioRxiv2020

Docosahexaenoic acid (DHA), a nutritional supplement, modulates steroid insensitivity in asthma

Asthmatics with poor steroid responsiveness are now found to use health services at higher frequency and contribute to socio-economic burden disproportionately. We have previously shown that a ω-6 fatty acid metabolite leads to a severe and steroid insensitive asthma-like condition in mice. Here, we investigated the role of retinoid-x-receptor gamma (RXRγ) and Docosahexaenoic acid (DHA), a ω3 fatty acid rexinoid ligand of RXR, on the features of steroid insensitivity in asthmatic condition. RXRγ was found to be reduced in the lungs of human asthmatics and mice with steroid insensitive allergic airway inflammation. RXRγ knockdown in naïve mice led to spontaneous asthma like features whereas RXRγ knockdown in allergic mice led to steroid insensitive asthma features. We observed while RXRγ binds to the glucocorticoid receptor (GR) gene and regulates its transcription, DHA increases the GRα expression in human bronchial epithelial cells and reverses the steroid insensitive features in mice with allergic airway inflammation. Docosahexaenoic acid (DHA), a ligand of RXR, was reduced in the sera of steroid-insensitive asthmatics. We conclude that DHA may prove to be a promising steroid sensitizing agent for the treatment of steroid insensitive asthmatics.Summary The molecular regulation of glucocorticoid receptor by retinoid-x-receptor gamma (RXRgama) has an implication in steroid insensitive asthma as we found that Docosahexaenoic acid (DHA), a nutritional supplement and natural ligand of RXRgamma, improves steroid sensitivity in steroid insensitive mice model of asthma and DHA levels are found to be low in steroid insensitive asthmatic patients.Competing Interest StatementThe authors have declared no competing interest.Abbreviations usedAAIAllergic airway inflammationAHRAirway hyper-responsivenessATRAAll-trans retinoic acidAUArbitrary unitsBALBronchoalveolar lavageBEAS-2BHuman bronchial epithelial cellsCECockroach allergen extractChIPChromatin Immunoprecipitation9CRA9-cis retinoic acidDEXDexamethasoneDHADocosahexaenoic acidDMSODimethyl sulfoxideELISAEnzyme-linked immunosorbent assayGAPDHGlyceraldehyde 3-phosphate dehydrogenaseGLucGaussia luciferaseGRαGlucocorticoid receptor alphaGREGlucocorticoid receptor elementH & EHaematoxylin and eosinIFNγInterferon gammaIgEImmunoglobulinE ILInterleukinKCKeratinocyte chemoattractant15-LOX15-lipoxygenaseMCF-7Human breast adenocarcinoma cell lineMCP1-αMonocyte chemoattractant protein1-αNF-κBNuclear Factor kappa-light-chain-enhancer of activated B cellsO.EOverexpressionOVAOvalbuminp38-MAPKp38 mitogen-activated protein kinasePBSPhosphate buffered salineRARRetinoic acid receptorPDTCPyrrolidinedithiocarbamateRXRERexinoid receptor elementRXRγRetinoid-x-receptor gamma13-S-HODE13-hydroxyoctadecadienoic acidSEMStandard error meansiRNASmall interfering RNASTAT-6Signal transducer and activator of transcription 6ThT helperVEHVehicleView Full Text

immunology↗