Implicación de igf1r en inflamación pulmonar aguda y en alergia inducida por ácaros del polvo doméstico en ratones stars

Abstract

Background: IGF1R (Insulin-like Growth Factor 1 Receptor) is a ubiquitous tyrosine kinase that modulates multiple cellular functions including proliferation, growth, differentiation and survival. Since prenatal Igf1r knockout mice die shortly after birth, the generation of Igf1r conditional mutant mice would allow to avoid postnatal mortality. IGFs were reported to play a role in chronic lung pathologies including cancer, ARDS, COPD, pulmonary fibrosis and asthma, in which inflammation is a relevant component. Methods: Igf1r deficiency was induced in four-week-old UBC-CreERT2; Igf1rfl/fl mice by five consecutive intraperitoneal tamoxifen (TMX) injections to generate UBC-CreERT2; Igf1rΔ/Δ (CreERT2) mice. Then, six-week-old CreERT2 male or female mice were intra-tracheally administered with a single dose of bleomycin (BLM) to study the implication of IGF1R in acute lung inflammation. In addition, eight- to 10-week-old female CreERT2 mice were intranasally challenged with house dust mite (HDM) five days per week for four weeks to study the implication of IGF1R in chronic asthma pathobiology. On the other hand, inbred C57BL/6 and CreERT2 mice were given daily consecutive doses of HDM extract to study the acute allergic profile and the implication of IGF1R in acute asthma pathobiology. Finally, IGF1R deficiency was therapeutically induced in mice to evaluate the resolution of allergic airway inflammation. Results: Unchallenged eight-week-old CreERT2 male mice showed a significant reduction of Igf1r expression in all organs analyzed, reflected in delayed body growth and reduced size of testes. Testes revealed halted spermatogenesis and liver and alveolar lung parenchyma showed increased cell proliferation rates. In addition, the lung transcriptome analysis of CreERT2 mice identified differentially expressed genes with potentially protective roles. After bleomycin-induced lung injury, CreERT2 mice demonstrated improved survival, reduced expression of pro-inflammatory markers, up-regulation of resolution indicators, decreased vascular fragility and permeability and reduced inflammatory cell presence in BALF and lungs and alveolar damage. Following chronic HDM exposure, CreERT2 mice exhibited increased expression of surfactant genes, no AHR, and a selective decrease in blood and BALF eosinophils, lung IL13 levels, airway collagen and smooth muscle thickness, as well as a significant depletion of goblet cell metaplasia and mucus secretion markers. Moreover, acute HDM exposure in inbred C57BL/6 mice led to a progressive increase in inflammatory cells in BALF, airway remodeling and mRNA expression of allergic airway inflammation and remodeling markers and preventively-induced Igf1r-deficiency in mice demonstrated reduced neutrophil and eosinophil numbers in BALF and bone marrow, decreased airway remodeling and depleted levels of associated molecular indicators. Additionally, therapeutic targeting of Igf1r in mice, promoted the resolution of allergic airway inflammation and remodeling. Conclusions: These findings support that IGF1R function is highly dependent on cell, tissue and organ type, and identify IGF1R as an important player in murine acute lung inflammation and HDM-driven allergic airway inflammation. Thus, IGF1R is suggested to be a promising candidate for future therapeutic approaches for the treatment of respiratory diseases with persistent damage and inflammation.