Characterization of the acute inflammatory profile and resolution of airway inflammation after Igf1r-gene targeting in a murine model of HDM-induced asthma

Abstract

Asthma is a chronic inflammatory disease characterized by bronchial hyperresponsiveness, mucus overproduction and airway remodeling. Notably, we have recently demonstrated that insulin-like growth factor 1 receptor (IGF1R) deficiency in mice attenuates airway hyperresponsiveness and mucus secretion after chronic house dust mite (HDM) exposure. On this basis, inbred C57BL/6 and Igf1r-deficient mice were given HDM extract to study the acute inflammatory profile and implication of Igf1r in acute asthma pathobiology. Additionally, Igf1r-deficiency was therapeutically induced in mice to evaluate the resolution of HDM-induced inflammation. Acute HDM exposure in inbred C57BL/6 mice led to a progressive increase in inflammation, airway remodeling and associated molecular indicators. Preventively-induced Igf1r-deficiency showed reduced neutrophil and eosinophil numbers in BALF and bone marrow, a significant reduction of airway remodeling and decreased levels of related markers. In addition, therapeutic targeting of Igf1r promoted the resolution of HDM-induced-inflammation. Our results demonstrate for the first time that Igf1r is important in acute asthma pathobiology and resolution of HDM-induced inflammation. Thus, IGF1R is suggested to be a promising candidate for future therapeutic approaches for the treatment and prevention of asthma.

IGF1R as a Potential Pharmacological Target in Allergic Asthma

“…In contrast, Igfbp2 and Igfbp4 expression depends solely on IGF1R activation since they were only found diminished by NVP treatment. Increased expression of Igf1 by HDM, which lowered to basal levels upon treatment with NVP, is in accordance with our previous findings [ 16 ]. HDM-mediated induction of Igf1 could be responsible for IGF1R phosphorylation to promote the asthmatic response, and therefore supports why targeting IGF1R with NVP ameliorates HDM-induced asthma.…”

“…HDM-induced allergy has been successfully proven for the study of asthma pathobiology [ 15 , 16 , 24 ]. Therefore, we deemed that our asthma model was appropriate for testing the in vivo anti-asthmatic efficacy of IGF1R inhibition using the IGF1R TKI inhibitor NVP-ADW742 (NVP).…”

“…In mice, IGF1 mediates allergic airway inflammation, and IGFBP3 was shown to block the effects of asthma [ 13 , 14 ]. Notably, we have reported that IGF1R plays a relevant role in initiation of the inflammatory response and that Igf1r -gene targeting in mice attenuates allergic airway inflammation [ 15 , 16 , 17 ].…”

Repeated exposure of house dust mite induces progressive airway inflammation in mice: Differential roles of CCL17 and IL‐13

“…16,17 HDM exerts its inflammatory response via Der p 1, 3, 5, and 9 antigens by stimulating airway epithelium to produce Th1/Th2 inflammatory response through protease-activated receptor-2 mediated mechanism. [18][19][20][21] While there are several commercial HDM allergens, we utilized Greer extract in our studies as it is one of the most characterized 12,18,22 and induces pronounced increases in CCL20, CCL17 and interleukin 5 accompanied by HDM-specific IgE, goblet cell hyperplasia, eosinophilic inflammation and airway hyper-reactivity. 23 In the present study, we attempted to systematically characterize HDM-induced F I G U R E 7 Expression of inflammatory genes in BAL cells after HDM challenge.…”

Niche Modulation of IGF-1R Signaling: Its Role in Stem Cell Pluripotency, Cancer Reprogramming, and Therapeutic Applications

“…In a model of asthma, a well-known inflammatory disease, Shao et al demonstrated that miR-133a is downregulated in this inflammatory niche and activates IGF-1R signaling, which is responsible for airway remodeling in asthma (Shao et al, 2019 ). IGF-1R deletion reduces the infiltration of immune cells as well as the expression of inflammation markers in the lung tissues in a murine model of asthma (Pineiro-Hermida et al, 2017 ). In addition, niche inflammation modulates IGF-1R signaling and affects local cellular responses.…”