Dendritic cell expression of the transcription factor T-bet regulates mast cell progenitor homing to mucosal tissue

The transcription factor T-bet was identified in CD4+ T cells, and it controls interferon γ production and T helper type 1 cell differentiation. T-bet is expressed in certain other leukocytes, and we recently showed (Lord, G.M., R.M. Rao, H. Choe, B.M. Sullivan, A.H. Lichtman, F.W. Luscinskas, and L.H. Glimcher. 2005. Blood. 106:3432–3439) that it regulates T cell trafficking. We examined whether T-bet influences homing of mast cell progenitors (MCp) to peripheral tissues. Surprisingly, we found that MCp homing to the lung or small intestine in T-bet−/− mice is reduced. This is reproduced in adhesion studies using bone marrow–derived MCs (BMMCs) from T-bet−/− mice, which showed diminished adhesion to mucosal addresin cellular adhesion molecule–1 (MAdCAM-1) and vascular cell adhesion molecule–1 (VCAM-1), endothelial ligands required for MCp intestinal homing. MCp, their precursors, and BMMCs do not express T-bet, suggesting that T-bet plays an indirect role in homing. However, adoptive transfer experiments revealed that T-bet expression by BM cells is required for MCp homing to the intestine. Furthermore, transfer of WT BM-derived dendritic cells (DCs) to T-bet−/− mice restores normal MCp intestinal homing in vivo and MCp adhesion to MAdCAM-1 and VCAM-1 in vitro. Nonetheless, T-bet−/− mice respond vigorously to intestinal infection with Trichinella spiralis, eliminating a role for T-bet in MC recruitment to sites of infection and their activation and function. Therefore, remarkably, T-bet expression by DCs indirectly controls MCp homing to mucosal tissues

Constitutive homing of mast cell progenitors to the intestine depends on autologous expression of the chemokine receptor CXCR2

Homing of mast cell progenitors (MCps) to the mouse small intestine involves the interaction of α4β7 integrin with mucosal addressin cellular adhesion molecule-1 (MAdCAM-1). We now demonstrate the dependence of this process on CXC chemokine receptor 2 (CXCR2) and vascular cell adhesion molecule-1 (VCAM-1) using null strains and mice sublethally irradiated and bone marrow (BM) reconstituted (SIBR) with wild-type or null BM or with wild-type BM followed by administration of blocking antibody. The intestinal MCp concentration in CXCR2-/- mice was reduced by 67%, but was unaltered in CC chemokine receptor 2-/- (CCR2-/-), CCR3-/-, or CCR5-/- mice. SIBR mice given CXCR2-/- BM had an intestinal MCp concentration that was 76% less than that in BALB/c BM reconstituted mice. Antibody blockade of VCAM-1 or of CXCR2 in SIBR mice reduced intestinal MCp reconstitution, and mice lacking endothelial VCAM-1 also had a marked reduction relative to wild-type mice. Finally, the half-life of intestinal MCps in wild-type mice was less than one week on the basis of a more than 50% reduction by administration of anti-α4β7 integrin or anti-CXCR2. Thus, the establishment and maintenance of MCps in the small intestine is a dynamic process that requires expression of the α4β7 integrin and the α-chemokine receptor CXCR2

Development of Mast Cells and Importance of Their Tryptase and Chymase Serine Proteases in Inflammation and Wound Healing

Mast cells (MCs) are active participants in blood coagulation and innate and acquired immunity. This review focuses on the development of mouse and human MCs, as well as the involvement of their granule serine proteases in inflammation and the connective tissue remodeling that occurs during the different phases of the healing process of wounded skin and other organs. The accumulated data suggest that MCs, their tryptases, and their chymases play important roles in tissue repair. While MCs initially promote healing, they can be detrimental if they are chronically stimulated or if too many MCs become activated at the same time. The possibility that MCs and their granule serine proteases contribute to the formation of keloid and hypertrophic scars makes them potential targets for therapeutic intervention in the repair of damaged skin

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

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 β7 integrin-deficient mice, recruitment was reduced 73% relative to wild-type controls, and in either BALB/c or C57BL/6 mice, mAb blocking of α4, β1, or β7 integrins inhibited the recruitment of MCp's to the inflamed lung. Thus, VCAM-1 interactions with both α4β1 and α4β7 integrins are essential for the recruitment and expansion of the MCp populations in the lung during antigen-induced pulmonary inflammation. Furthermore, the MCp is currently unique among inflammatory cells in its partial dependence on α4β7 integrins for lung recruitment

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

Mast cells participate in pathophysiological processes that range from antimicrobial defense to anaphylaxis and inflammatory arthritis. Much of the groundwork for the understanding of mast cells was established in mice that lacked mast cells through defects in either stem cell factor or its receptor, Kit. Among available strains, C57BL/6-KitW-sh (Wsh) mice are experimentally advantageous because of their background strain and fertility. However, the genetic inversion responsible for the Wsh phenotype remains poorly defined, and its effects beyond the mast cell have been incompletely characterized. We report that Wsh animals exhibit splenomegaly with expanded myeloid and megakaryocyte populations. Hematopoietic abnormalities extend to the bone marrow and are reflected by neutrophilia and thrombocytosis. In contrast, mast cell-deficient WBB6F1-KitW/KitW-v (W/Wv) mice display mild neutropenia, but no changes in circulating platelet numbers. To help define the basis for the Wsh phenotype, a “DNA walking” strategy was used to identify the precise location of the 3′ breakpoint, which was found to reside 67.5 kb upstream of Kit. The 5′ breakpoint disrupts corin, a cardiac protease responsible for the activation of atrial natriuretic peptide. Consistent with this result, transcription of full-length corin is ablated and Wsh mice develop symptoms of cardiomegaly. Studies performed using mast cell-deficient strains must consider the capacity of associated abnormalities to either expose or compensate for the missing mast cell lineage