Alpha-4 integrins and VCAM-1, but not MAdCAM-1, are essential for recruitment of mast cell progenitors to the inflamed lung

Abstract

Normal mouse lungs lack appreciable numbers of mast cells (MCs) or MC progenitors (MCp's), yet the appearance of mature MCs in the tracheobronchial epithelial surface is a characteristic of allergic, T-cell-dependent pulmonary inflammation. We hypothesized that pulmonary inflammation would recruit MCp's to inflamed lungs and that this recruitment would be regulated by distinct adhesion pathways. Ovalbumin-sensitized and challenged mice had a greater than 28-fold increase in the number of MCp's in the lungs. In mice lacking endothelial vascular cell adhesion molecule 1 (VCAM-1) and in wild-type mice administered blocking monoclonal antibody (mAb) to VCAM-1 but not to mucosal addressin CAM-1 (MadCAM-1), recruitment of MCp's to the inflamed lung was reduced by greater than 75%. Analysis of the integrin receptors for VCAM-1 showed that in ␤7 integrin-deficient mice, recruitment was reduced 73% relative to wild-type controls, and in either BALB/c or C57BL/6 mice, mAb blocking of ␣4, ␤1, or ␤7 IntroductionMast cells (MCs) develop in tissues from bone marrow-derived MC progenitors (MCp's) drawn from the intravascular compartment. The intestine has an abundant supply of MCs, and MCp's constitutively home to this organ. In contrast, the naive mouse lung has few MCp's and lacks mature MCs beyond first-and secondgeneration bronchi. [1][2][3] Nonetheless, MCs accumulate in the epithelial surfaces of both large and small bronchi of mice that are sensitized systemically with ovalbumin (OVA) and challenged repetitively by aerosol inhalation to generate chronic airway inflammation. 3 Furthermore, MCs are required for the development of airway hyperresponsiveness to methacholine in protocols that lack adjuvant or otherwise limit the intensity of sensitization before challenge with OVA. [4][5][6] In humans with bronchial asthma, MCs accumulate and degranulate in both the bronchial epithelium and airway smooth muscle, 7-9 accompanied by increased numbers of MCp's in the blood. 10 Treatment with humanized monoclonal antibody (mAb) that blocks access of serum IgE to the high-affinity Fc⑀RI receptor reduces the frequency of asthma exacerbations. 11 These findings imply a pathophysiologic role for MCs and their expansion both in mouse models of airway inflammation and in the pathogenesis of human bronchial asthma.Although the small airways of the mouse have scant smooth muscle, little lamina propria, and negligible bronchial circulation compared with those of the human, an increment in intraepithelial MCs and leukocyte infiltrates around bronchovascular bundles is consistently observed in inflamed respiratory mucosal surfaces in both species, leading to the suggestion that the site of extravasation is via the associated microvasculature. 12,13 It is thus likely that the pathways needed for incremental MC numbers are conserved. Moreover the low levels of MCp's and scarcity of mature MCs in the naive mouse lung suggest that MCp recruitment accounts for the MC accumulation in the bronchial mucosa with the induction of allergic inflammat...

CD11c+ Cells Are Required for Antigen-Induced Increase of Mast Cells in the Lung

“…Naive mice, or mice sensitized to an Ag but not challenged, have few MCp and mature mast cells in the airways (10)(11)(12). However, when sensitized mice are challenged, the influx of MCp to the lung increases 10-to 30-fold (10,12). This is followed by an increase in mature mast cells in the tracheal intraepithelium 1 wk later (11).…”

“…During normal conditions these home to peripheral organs via the blood and mature in situ (9). Naive mice, or mice sensitized to an Ag but not challenged, have few MCp and mature mast cells in the airways (10)(11)(12). However, when sensitized mice are challenged, the influx of MCp to the lung increases 10-to 30-fold (10,12).…”

Mast Cell Fibroblastoid Differentiation Mediated by Airway Smooth Muscle in Asthma

“…Mast cell progenitor recruitment to the lung is in part mediated by leukotriene B4 (9) and chemokines (10) and is integrin dependent (11). In the airway, mast cell trafficking to different compartments is under the influence of several chemotactic factors (reviewed in Ref.…”

Chemotactic action of prostaglandin E2on mouse mast cells acting via the PGE2receptor 3

“…Trafficking of mast cell progenitors to the small intestine requires ␣ 4 ␤ 7 integrin interaction with endothelial mucosal addresin cellular adhesion molecule-1 (MAdCAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells (18), and mast cell progenitor recruitment to the lungs is mediated by ␣ 4 ␤ 7 and␣ 4 ␤ 1 integrin interaction with VCAM-1 (19).…”