The Hexosamine Biosynthetic Pathway Links Innate Inflammation With Epithelial-Mesenchymal Plasticity in Airway Remodeling

Abstract

Disruption of the lower airway epithelial barrier plays a major role in the initiation and progression of chronic lung disease. Here, repetitive environmental insults produced by viral and allergens triggers metabolic adaptations, epithelial-mesenchymal plasticity (EMP) and airway remodeling. Epithelial plasticity disrupts epithelial barrier function, stimulates release of fibroblastic growth factors, and remodels the extracellular matrix (ECM). This review will focus on recent work demonstrating how the hexosamine biosynthetic pathway (HBP) links innate inflammation to airway remodeling. The HBP is a core metabolic pathway of the unfolded protein response (UPR) responsible for protein N-glycosylation, relief of proteotoxic stress and secretion of ECM modifiers. We will overview findings that the IκB kinase (IKK)-NFκB pathway directly activates expression of the SNAI-ZEB1 mesenchymal transcription factor module through regulation of the Bromodomain Containing Protein 4 (BRD4) chromatin modifier. BRD4 mediates transcriptional elongation of SNAI1-ZEB as well as enhancing chromatin accessibility and transcription of fibroblast growth factors, ECM and matrix metalloproteinases (MMPs). In addition, recent exciting findings that IKK cross-talks with the UPR by controlling phosphorylation and nuclear translocation of the autoregulatory XBP1s transcription factor are presented. HBP is required for N glycosylation and secretion of ECM components that play an important signaling role in airway remodeling. This interplay between innate inflammation, metabolic reprogramming and lower airway plasticity expands a population of subepithelial myofibroblasts by secreting fibroblastic growth factors, producing changes in ECM tensile strength, and fibroblast stimulation by MMP binding. Through these actions on myofibroblasts, EMP in lower airway cells produces expansion of the lamina reticularis and promotes airway remodeling. In this manner, metabolic reprogramming by the HBP mediates environmental insult-induced inflammation with remodeling in chronic airway diseases.

Metabolism-driven glycosylation represents therapeutic opportunities in interstitial lung diseases

“…Finally, UDP-N-acetylhexosamine pyrophorylase (UAP) synthesizes UDP-GlcNAc and diphosphate from N-acetylglucosamine-1-phosphate and uridine triphosphate (UTP). Crucial enzymes within the HBP pathway such as (GFAT1, GNA1, PGM3) are elevated in a process shared by various ILDs, namely when epithelial-mesenchymal plasticity (EMP) is induced by TGF-β ( 100 ). This elevation is necessary for the N-glycosylation process and subsequent secretion of extracellular matrix (ECM) components, which is vital for airway remodeling, highlighting fibrosis-promoting role of the HBP pathway.…”

Epigenetic Regulation of EMP/EMT-Dependent Fibrosis

“…The studies conducted in order to evaluate a possible connection between epigenetics, EMP, and fibrosis are leading to the first discoveries, for example, in airway persistent inflammation [ 95 ], but require further investigation. On the contrary, the field of studies conducted on the role of epigenetic modifications in EMT-dependent fibrosis is much more flourishing.…”

Cooperative interaction of interferon regulatory factor -1 and bromodomain—containing protein 4 on RNA polymerase activation for intrinsic innate immunity

“…These entities activate pattern recognition receptors (PRRs) retinoic acid inducible gene-I (RIGI) and Toll-like receptor 3 (TLR3) ( 15 – 17 ) that form active TANK-Binding Kinase and IκB Kinase (IKK) signalsomes, stimulating interferon regulatory factor (IRF1), activating protein 1 (AP1) and NF-κB ( 17 – 19 ). More recent work has shown that RSV is also a potent activator of the unfolded protein response that results in inducible phenotypic changes known as “epithelial plasticity” and upregulation of N-glycosylation pathways controlling extracellular matrix production and mucin secretion ( 20 , 21 ). The exuberant, innate response of small airways epithelium explains the observations that, in fatal cases of RSV LRTI, acute hypoxic respiratory failure is associated with mucus plugging and ventilation-perfusion mismatch in the small airways ( 11 ).…”