Modulation of ILC2 trafficking and effector functions in ILC2-driven airway hyperreactivity

Abstract

Abstract Background Asthma is a heterogeneous disease of the airways characterized by increased airway hyperreactivity (AHR) to specific and unspecific stimuli. Group 2 innate lymphoid cells (ILC2s) are type 2 secreting cells that are sufficient to induce eosinophilic lung inflammation and AHR independent of adaptive immunity in murine models. Identifying pathways that modulate ILC2 homeostasis and function are therefore an important step towards treating ILC2-dependent asthma. Objective We examined the expression of adhesion molecule lymphocyte-associated antigen 1 (LFA-1) and ligand intercellular adhesion molecule (ICAM)-1 on ILC2s and their effect on the development of lung inflammation and AHR in murine models. Methods Genetically modified mice constitutively lacking LFA-1 or ICAM-1 were assessed for the development of lung inflammation and AHR. We further generated mixed bone marrow chimeras and performed transcriptomic analysis to characterize their role on ILC2 homeostasis and function. Results LFA-1 is expressed on murine naïve and IL-33-activated ILC2s, while ICAM-1 is surprisingly expressed – and upregulated – upon activation. Compared to WT mice, both LFA-1−/− and ICAM-1−/− mice develop less lung inflammation and AHR in response to intranasal IL-33 challenge. Furthermore, experiments with chimeric mice revealed that LFA-1−/− ILC2s significantly traffic less to the lungs, unlike ICAM-1−/− ILC2s. Strikingly, ICAM-1−/− ILC2s however show a defect in proliferation and cytokine production, ultimately affecting lung inflammation. Conclusions The LFA-1-ICAM-1 interaction is involved in lung ILC2 trafficking, homeostasis and function. Such findings could lead to the development of new therapeutic targets.