CD34 facilitates the development of allergic asthma

Abstract

Asthma is a pulmonary inflammatory disease dependent on eosinophil and mast cell infiltration into the lung. CD34 is a sialomucin expressed by both of these cell types, and we have used CD34 Ϫ/Ϫ mice and a standard mouse model of asthma to evaluate the importance of CD34 expression on disease development. In comparison with wild-type (wt) mice, CD34 Ϫ/Ϫ mice exhibited a dramatic reduction in all hallmarks of allergic asthma, including lowered airway inflammatory cell infiltration, airway hyperresponsiveness, and mast-cell recruitment. Bone marrow transplantation experiments confirmed that these defects are due to CD34 expression by bone marrow-derived cells. This was not, however, due to an inability to respond to antigen as, on a per cell basis, wt and CD34 Ϫ/Ϫ inflammatory cells exhibit identical responses in cytokine production. We found a striking reduction in mobility of CD34 Ϫ/Ϫ eosinophils in vitro, the major component of inflammatory infiltrates, which was consistent with proposed models for CD34 as an inhibitor of cell-cell adhesion. In summary, our data suggest that CD34 enhances mast-cell and eosinophil invasiveness and that its expression by these cells is a prerequisite for development of allergic asthma. (Blood.

SHIP1 Is a Repressor of Mast Cell Hyperplasia, Cytokine Production, and Allergic Inflammation In Vivo

“…In our studies, we also found that Ship1 Ϫ/Ϫ -BMMC mice suffered worse allergic asthma pathology than Ship1 ϩ/ϩ -BMMC mice in an acute, OVA-induced (with alum adjuvant) model of allergic asthma (28). Because Kit W-sh/W-sh mice also developed symptoms of asthma, it made it difficult to determine to what extent Ship1 Ϫ/Ϫ mast cells were proinflammatory or whether they instead lacked the anti-inflammatory activity present in Ship1 ϩ/ϩ mast cells.…”

Mast cells are an essential hematopoietic component for polyp development

“…We have previously shown that CD34 and the related antigen CD43 are essential for the recruitment of MC precursors to peripheral tissues (24). More recent studies using inflammatory models suggest that loss of CD34 alone in many cases is sufficient to impede recruitment of MC precursors to peripheral tissues (8).…”

“…c-kit is a well known MC growth factor receptor, and mice bearing an inversion of the promoter (Kit Wsh/Wsh ) exhibit a selective defect in the ability to form mature MC. CD34 and CD43 are related cell surface sialomucins, and, although deletion of these genes has no effect on MCp formation in the BM, their loss leads to a profound impairment in the ability of MCp to traffic to peripheral tissues (8,24). To generate chimeras, APC ⌬468 mice were lethally irradiated and reconstituted with wt, Kit Wsh/Wsh or Cd34 Ϫ/Ϫ Cd43 Ϫ/Ϫ BM and analyzed 6 weeks later for polyps.…”

“…They elaborate a potent array of cytokines, proteases, and inflammatory mediators (including TNF␣, IL-6, TGF-␤, VEGF, MMP2, and MMP9), which are known to be involved in tissue remodeling and angiogenesis. These cells are responsive to CCL9, and we have recently shown that they require the sialomucin CD34 (and CD43) for efficient trafficking in vivo (7,8). Although mastocytosis is frequently associated with the emergence of tumors (6)(7)(8)(9)(10)(11)(12)(13), their role in tumor progression or rejection is only beginning to be studied.…”

A humanized microbiota mouse model of ovalbumin-induced lung inflammation

“…Experimental murine lung inflammation was induced in mice previously colonized with murine or human feces, as previously described 17 with minor modifications. Although this model does not fully recapitulate the phenotype of human allergic asthma, it is a useful model for evaluating many aspects of this lung inflammatory disease.…”