Absence of insulin receptor substrate 2 (IRS2) in myeloid cells results in enhanced hypoxia-induced remodeling of the pulmonary vasculature and heart with modest effects on allergic lung inflammation.

Abstract

We previously reported that global insulin receptor substrate-2 (IRS2)-deficient mice demonstrated enhanced pulmonary vascular remodeling in response to allergen exposure or to hypoxia. To evaluate the specific contribution of IRS2 in myeloid cells to this process, we analyzed responses in mice with conditional IRS2-deficiencies in myeloid cells by crossing Irs2fl/fl mice to LysM-Cretg/wt mice and examined responses to allergens and hypoxia. There were no significant differences in the allergic inflammatory response induced by either ovalbumin adsorbed to aluminum hydroxide or by house dust mite (HDM) between Irs2fl/flLysM-Crewt/wt (Cre-/-) and Irs2fl/flLysM-Cretg/wt (Cre+/-) littermates. However, there was a significant difference between Cre-/- and Cre+/- mice in the HDM-induced remodeling of small pulmonary blood vessels. Such remodeling can lead to changes in cardiopulmonary function including increases in right ventricular systolic pressure (RVSP) and pulmonary hypertension (PH). While we did observe an increase in RVSP in response to hypoxia or allergen, there was no significant difference in RSVP between Cre-/- and Cre+/- mice. However, there was a significant difference in right heart remodeling as indicated by changes in right ventricular internal diameter and Fulton Index. These results indicate that IRS2 expression in myeloid cells limits pulmonary and cardiac remodeling responses that are induced by allergic inflammation or hypoxia.