Pulmonary CXCR2 regulates VCAM-1 and antigen-induced recruitment of mast cell progenitors.
ABSTRACT Chemokine receptors regulate the trafficking of leukocytes by mediating chemotaxis and by their influence on the expression and/or affinity of leukocyte integrins. Using blocking mAb, we showed that antigen-induced recruitment of mast cell progenitors (MCp) to the lung requires interaction of a4 integrins on the MCp with endothelial vascular cell adhesion molecule 1 (VCAM-1). In seeking a chemokine component, we found that CXCR2-deficient but not CCR3- or CCR5-deficient sensitized and antigen-challenged mice have significantly fewer lung MCp 1 day after challenge and fewer tracheal intraepithelial MC 1 week after challenge, implying that recruited MCp provide the source for these mature MC. Unexpectedly, reconstitution of sensitized, sublethally irradiated +/+ and -/- mice with bone marrow cells of either genotype indicated that expression of CXCR2 by the migrating MCp was not required. Instead, receptor function by resident lung cells was required because normal BM did not reconstitute MCp recruitment in irradiated CXCR2(-/-) mice. The reduced MCp influx into the lung of CXCR2(-/-) mice was accompanied by reduced induction of VCAM-1 transcripts and reduced endothelial surface expression. Thus, these studies demonstrate a role for a chemokine receptor in regulating endothelial VCAM-1 expression, MCp migration, and the level of intraepithelial MC in the lung of aerosolized, antigen-challenged mice.
Article: Vascular cell adhesion molecule-1 expression and signaling during disease: regulation by reactive oxygen species and antioxidants.[show abstract] [hide abstract]
ABSTRACT: The endothelium is immunoregulatory in that inhibiting the function of vascular adhesion molecules blocks leukocyte recruitment and thus tissue inflammation. The function of endothelial cells during leukocyte recruitment is regulated by reactive oxygen species (ROS) and antioxidants. In inflammatory sites and lymph nodes, the endothelium is stimulated to express adhesion molecules that mediate leukocyte binding. Upon leukocyte binding, these adhesion molecules activate endothelial cell signal transduction that then alters endothelial cell shape for the opening of passageways through which leukocytes can migrate. If the stimulation of this opening is blocked, inflammation is blocked. In this review, we focus on the endothelial cell adhesion molecule, vascular cell adhesion molecule-1 (VCAM-1). Expression of VCAM-1 is induced on endothelial cells during inflammatory diseases by several mediators, including ROS. Then, VCAM-1 on the endothelium functions as both a scaffold for leukocyte migration and a trigger of endothelial signaling through NADPH oxidase-generated ROS. These ROS induce signals for the opening of intercellular passageways through which leukocytes migrate. In several inflammatory diseases, inflammation is blocked by inhibition of leukocyte binding to VCAM-1 or by inhibition of VCAM-1 signal transduction. VCAM-1 signal transduction and VCAM-1-dependent inflammation are blocked by antioxidants. Thus, VCAM-1 signaling is a target for intervention by pharmacological agents and by antioxidants during inflammatory diseases. This review discusses ROS and antioxidant functions during activation of VCAM-1 expression and VCAM-1 signaling in inflammatory diseases.Antioxidants & Redox Signaling 11/2010; 15(6):1607-38. · 8.20 Impact Factor
Article: IgE immune complexes stimulate an increase in lung mast cell progenitors in a mouse model of allergic airway inflammation.[show abstract] [hide abstract]
ABSTRACT: Mast cell numbers and allergen specific IgE are increased in the lungs of patients with allergic asthma and this can be reproduced in mouse models. The increased number of mast cells is likely due to recruitment of mast cell progenitors that mature in situ. We hypothesized that formation of IgE immune complexes in the lungs of sensitized mice increase the migration of mast cell progenitors to this organ. To study this, a model of allergic airway inflammation where mice were immunized with ovalbumin (OVA) in alum twice followed by three daily intranasal challenges of either OVA coupled to trinitrophenyl (TNP) alone or as immune complexes with IgE-anti-TNP, was used. Mast cell progenitors were quantified by a limiting dilution assay. IgE immune complex challenge of sensitized mice elicited three times more mast cell progenitors per lung than challenge with the same dose of antigen alone. This dose of antigen challenge alone did not increase the levels of mast cell progenitors compared to unchallenged mice. IgE immune complex challenge of sensitized mice also enhanced the frequency of mast cell progenitors per 10(6) mononuclear cells by 2.1-fold. The enhancement of lung mast cell progenitors by IgE immune complex challenge was lost in FcRγ deficient mice but not in CD23 deficient mice. Our data show that IgE immune complex challenge enhances the number of mast cell progenitors in the lung through activation of an Fc receptor associated with the FcRγ chain. This most likely takes place via activation of FcεRI, although activation via FcγRIV or a combination of the two receptors cannot be excluded. IgE immune complex-mediated enhancement of lung MCp numbers is a new reason to target IgE in therapies against allergic asthma.PLoS ONE 01/2011; 6(5):e20261. · 4.09 Impact Factor