Pulmonary CXCR2 regulates VCAM-1 and antigen-induced recruitment of mast cell progenitors

Abstract

chemokine receptors ͉ endothelium ͉ lung inflammation T he bronchial inflammation in atopic asthma and in allergeninduced mouse models of pulmonary inflammation is characterized by the influx of various effector cell populations including Th2 cells, eosinophils, basophils, and mast cells (MC). The MC numbers increase both in the smooth muscle and in the epithelium of the airways of humans with atopic asthma (1, 2). Moreover, there is marked hyperplasia of intraepithelial (IE) MC in mice with antigen-induced Th2-mediated inflammation of the airways, although normal mouse lung lacks appreciable numbers of MC (3, 4). That antigen-induced airways hyperreactivity is diminished in MC-deficient strains indicates the importance of the MC to the biology of the host response (3, 5).Recruitment of MC progenitors (MCp) to the lung of sensitized, aerosolized antigen-challenged BALB/c mice is rapid and depends on expression of ␣4␤1 or ␣4␤7 integrins because this response was blocked by mAb to these integrins, with the counterligand being vascular cell adhesion molecule 1 (VCAM-1) (6). Because transendothelial migration of cells into tissues characteristically involves not only adhesion but also directed migration, we turned our attention to possible chemokine receptors on the MCp. Using null mouse strains lacking CCR3, CCR5, or CXCR2, which are known to be expressed by cultured mouse bone marrow-derived MC (mBMMC) and/or by human cord blood-derived MC (7-9), we investigated the requirement for these receptors on MCp recruitment to antigensensitized and challenged mice. We find that MCp recruitment to the lung of sensitized, BALB/c mice after three daily aerosolized antigen challenges depends on CXCR2 function in the lung parenchyma/microvasculature rather than on the MCp with selectivity for the MCp relative to other mononuclear cells. The deficiency in CXCR2 is associated with a reduction in VCAM-1 expression in the lung and with a reduction in the subsequent appearance of mature mucosal MC in the trachea, suggesting that the recruitment is a prerequisite for the IE MC hyperplasia. Results Reduced MCp Recruitment to Lung of Sensitized and Antigen-Challenged CXCR2 ؊/؊ Mice. We demonstrated that MCp recruitment to the lung of ovalbumin (OVA)-sensitized and aerosolized OVA-challenged BALB/c mice approaches a plateau after only three daily challenges (6). To evaluate any effect resulting from the loss of expression of a chemokine receptor, the numbers of mononuclear cells (MNC) and MCp in the lung of sensitized, antigen-challenged wild-type (WT) (BALB/c) and CXCR2-null mice were compared. Sensitized WT and CXCR2 Ϫ/Ϫ mice that were not challenged with aerosolized antigen show similar low levels of MNC and MCp in the lung as noted previously (Fig.

Genetic Inversion in Mast Cell-Deficient Wsh Mice Interrupts Corin and Manifests as Hematopoietic and Cardiac Aberrancy

“…As a consequence, W sh mice exhibit cardiac hypertrophy, a phenotype characteristic of corin-deficient mice ( Figure 6E). 24 These data confirm that the mutation underlying the W sh phenotype interrupts corin between exons 5 and 6, and encompasses 27 other genes in an inversion spanning approximately 3.1 Mb (Table 1). We cannot exclude the loss of a limited amount of genetic material at the newly 5Ј end of Gray nucleotides belong to inverted corin, underlined and italicized bases are insertions and black nucleotides are bases upstream of Kit unaffected by inversion.…”

“…The mast cell colonies with their distinct morphology were counted at 10 to 14 days. While committed mast cell progenitors have typically been enumerated in peripheral tissues with this technique, 24 myeloid progenitors upstream of committed mast cell progenitors that are SCF-and/or interleukin-3-responsive would also be expected to form colonies in this assay. 25 Thus this assay enumerates the cells capable of giving rise to committed mast cells within this tissue.…”

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

“…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). Therefore, the allergen-induced increase in mature lung mast cells seen in both asthmatic patients and in mouse models is presumably preceded by an increased migration of MCp into the lung, referred to in this study as MCp recruitment.…”

“…+ cells are required for MCp recruitment to the lung in sublethally irradiated wild-type mice reconstituted with CD11c-DTR bone marrow Previous studies have demonstrated that the Ag-induced recruitment of lung MCp is followed by intraepithelial mast cells that appear in the trachea 1 wk after challenge (11). To investigate whether the absence of CD11c + cells during the challenge phase leads to reduced numbers of mature mast cells in the airways, we therefore had to wait 11 d after the first DT treatment.…”

“…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).…”