Age dictates a steroid-resistant cascade of Wnt5a, transglutaminase 2, and leukotrienes in inflamed airways

Abstract

Our findings reveal age differences in LT and Wnt pathways during airway inflammation and identify a steroid-resistant cascade of Wnt5a, Tgm2, and LTs, which might represent a therapeutic target for airway inflammation and remodeling.

Eicosanoids in tissue repair

“…As an alternative to the COX pathway, AA can be metabolized via LOX enzymes, giving rise to hydroxyeicosatetraenoic acids (HETEs), LTs or lipoxins. Together with myeloid cells, which can release large amounts of LTs upon cellular damage, epithelial cells have been implicated more recently in the production of LTs in settings of inflammation and tissue remodeling, particularly in the lung . In the intestine, LT biosynthetic enzymes are also expressed by (epithelial) tuft cells (also called brush cells), which have recently been implicated in the induction of type 2 immune responses .…”

“…Thus, the recruitment of eosinophils and cells of the monocyte/ macrophage lineage during the inflammatory and proliferative phase of tissue repair results in a second wave of cysLTs, which has been linked to pathological remodeling, for example in asthma or fibrosis. During these later phases of tissue repair, stromal cells produce various mediators of tissue remodeling (including TGFβ1, wnt5A and transglutaminase 2 (TG2)), which can promote the generation of cysLTs by myeloid cells . cysLTs produced by myeloid cells or damaged epithelium can stimulate collagen production by (myo‐)fibroblasts by activating their high‐affinity receptor (CysLT1R) .…”

“…Moreover, the administration of LXA 4 ‐containing microparticles in a rat model of skin wound healing promoted wound closure, angiogenesis and collagen deposition, potentially by inducing IL‐4, TGFβ1 and tissue repair macrophages . Intriguingly, 12‐/15‐LOX is generally highly expressed during type 2 immune responses, for example after exposure to house dust mite or during intestinal nematode infection . This may suggest that 12/15‐LOX also plays important roles in epithelial barrier repair in mucosal tissues such as the airways and intestine.…”

“…Together with myeloid cells, which can release large amounts of LTs upon cellular damage, epithelial cells have been implicated more recently in the production of LTs in settings of inflammation and tissue remodeling, particularly in the lung. 15 In the intestine, LT biosynthetic enzymes are also expressed by (epithelial) tuft cells (also called brush cells), which have recently been implicated in the induction of type 2 immune responses. 16 In addition to 5-LOX, the synthesis of bioactive LTs [LTB 4…”

Endotypes in Chronic Rhinosinusitis: Biomarkers Based on a Mechanistic Insight for Targeted Treatment?

“…The expression of TGM2 by stromal cells in nasal polyp tissue may even help to define differences in type 2 cytokine-high endotypes, and help to differentiate, for instance, between response to house dust mites and AERD [31] . Another promising candidate marker for AERD endotypes is DPP-10 (dipeptidyl peptidase 10) polymorphism [32] , where serum testing is in the pilot stage.…”