ABSTRACT: Chronic exposure to fluticasone propionate shapes gene expression and modulates innate and adaptive activation pathways in human macrophages (LPS)
Project description:Chronic exposure to fluticasone propionate shapes gene expression and modulates innate and adaptive activation pathways in human macrophages
Project description:Chronic exposure to fluticasone propionate shapes gene expression and modulates innate and adaptive activation pathways in human macrophages (INF)
Project description:Here we investigate how glucocorticoids affect the response to LPS in human macrophages. Total RNA obtained from monocyte-derived macrophages exposed to lipopolysacharide presceding exposure to fluticasone propionate or left untreated.
Project description:Here we investigate how glucocorticoids affect the response to Interferon gamma in human macrophages. Total RNA obtained from monocyte-derived macrophages exposed to Interferon gamma presceding exposure to fluticasone propionate or left untreated.
Project description:The effects of inhaled corticosteroids (ICS) on healthy airways are poorly defined. Our objective was to delineate the effects of ICS on gene expression in healthy airways, without confounding caused by changes in disease-related genes and disease-related alterations in ICS-responsiveness. We performed a randomised open-label bronchoscopy study of high dose ICS therapy in 30 healthy adult volunteers randomised 2:1 to i) fluticasone propionate 500 mcg bd or ii) no treatment (control), for 4 weeks. Laboratory staff were blinded to allocation. Biopsies and brushings were analysed by bulk RNA sequencing. ICS treatment upregulated 72 genes in brushings and 53 genes in biopsies, and downregulated 82 genes in brushings and 416 genes in biopsies. The most downregulated genes in both tissues were canonical markers of type-2 inflammation (FCER1A, CPA3, IL33, CLEC10A, SERPINB10 and CCR5), T cell-mediated adaptive immunity (TARP, TRBC1, TRBC2, PTPN22, TRAC, CD2, CD8A, HLA-DQB2, CD96, PTPN7), B cell immunity (CD20, immunoglobulin heavy and light chains), and innate immunity, including CD48, Hobit, RANTES, Langerin and GFI1. An IL-17-dependent gene signature was not upregulated by ICS. In healthy airways, 4-week ICS exposure reduces gene expression related to both innate and adaptive immunity, and reduces markers of type-2 inflammation. This implies that homeostasis in health involves tonic type-2 signalling in the airway mucosa, which is exquisitely sensitive to ICS.
Project description:Rationale: Lipopolysaccharide (LPS) is ubiquitous in the environment. Inhalation of LPS has been implicated in the pathogenesis and/or severity of several lung diseases, including pneumonia, chronic obstructive pulmonary disease and asthma. Alveolar macrophages are the main resident leukocytes exposed to inhaled antigens. Objectives: To obtain insight into which innate immune pathways become activated within human alveolar macrophages upon exposure to LPS in vivo.
Project description:We collected airway epithelial brushings for microarray analysis from 42 asthmatics and two control groups â 28 healthy subjects and 16 smokers. A subgroup of 32 asthmatics completed a randomized placebo-controlled trial of fluticasone propionate in which collection of brushings was repeated after 1 week of treatment. Experiment Overall Design: 1) Comparison of gene expression in asthmatics to healthy controls Experiment Overall Design: 2) Comparison of smokers to healthy controls Experiment Overall Design: 3) Comparison of change in gene expression in the fluticasone treated group to the change in the placebo treated group
Project description:While Δ⁹-Tetrahydrocannabinol (THC), is known for its psychoactive effects, its role in modulating complex innate immune cascades remains poorly defined. In this study, we integrated transcriptomic, cellular, and in vivo approaches to investigate how THC regulates lipopolysaccharide (LPS) induced inflammation. Using human THP-1 monocytic cells, we found that THC independently induces a stress-adaptive transcriptional program upregulating genes associated with the unfolded protein response (UPR) and autophagy pathways while robustly suppressing LPS-induced Type-I interferon stimulated genes (ISGs) and pro-inflammatory cytokines such as IL-1β and TNF-α. These results were corroborated in primary human monocytes, where THC significantly reduced the expression of activation markers CD80, CD83, and CD209. In a murine model of systemic inflammation, chronic THC exposure attenuated the activation of splenic myeloid and T cells. Notably, RNA-seq analysis of brain tissue revealed that THC dampened neuroinflammatory gene expression while promoting pathways linked to neurogenesis and synaptic plasticity. Our findings suggest that THC reprograms innate immune cells toward a metabolically adaptive phenotype that limits excessive activation in both the periphery and the central nervous system. This dual action provides a mechanistic framework for the therapeutic potential of cannabinoids in treating chronic inflammatory and neuroimmune disorders.
