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1.  VEGF controls lung Th2 inflammation via the miR-1–Mpl (myeloproliferative leukemia virus oncogene)–P-selectin axis 
The Journal of Experimental Medicine  2013;210(10):1993-2010.
VEGF dampens the expression of microRNA-1, which drives inflammation in part via increasing the expression of Mpl.
Asthma, the prototypic Th2-mediated inflammatory disorder of the lung, is an emergent disease worldwide. Vascular endothelial growth factor (VEGF) is a critical regulator of pulmonary Th2 inflammation, but the underlying mechanism and the roles of microRNAs (miRNAs) in this process have not been defined. Here we show that lung-specific overexpression of VEGF decreases miR-1 expression in the lung, most prominently in the endothelium, and a similar down-regulation occurs in lung endothelium in Th2 inflammation models. Intranasal delivery of miR-1 inhibited inflammatory responses to ovalbumin, house dust mite, and IL-13 overexpression. Blocking VEGF inhibited Th2-mediated lung inflammation, and this was restored by antagonizing miR-1. Using mRNA arrays, Argonaute pull-down assays, luciferase expression assays, and mutational analysis, we identified Mpl as a direct target of miR-1 and showed that VEGF controls the expression of endothelial Mpl during Th2 inflammation via the regulation of miR-1. In vivo knockdown of Mpl inhibited Th2 inflammation and indirectly inhibited the expression of P-selectin in lung endothelium. These experiments define a novel VEGF–miR-1–Mpl–P-selectin effector pathway in lung Th2 inflammation and herald the utility of miR-1 and Mpl as potential therapeutic targets for asthma.
doi:10.1084/jem.20121200
PMCID: PMC3782056  PMID: 24043765
2.  Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung 
Nature medicine  2004;10(10):1095-1103.
Exaggerated levels of VEGF (vascular endothelial growth factor) are present in persons with asthma, but the role(s) of VEGF in normal and asthmatic lungs has not been defined. We generated lung-targeted VEGF165 transgenic mice and evaluated the role of VEGF in T-helper type 2 cell (TH2)-mediated inflammation. In these mice, VEGF induced, through IL-13–dependent and –independent pathways, an asthma-like phenotype with inflammation, parenchymal and vascular remodeling, edema, mucus metaplasia, myocyte hyperplasia and airway hyper-responsiveness. VEGF also enhanced respiratory antigen sensitization and TH2 inflammation and increased the number of activated DC2 dendritic cells. In antigen-induced inflammation, VEGF was produced by epithelial cells and preferentially by TH2 versus TH1 cells. In this setting, it had a critical role in TH2 inflammation, cytokine production and physiologic dysregulation. Thus, VEGF is a mediator of vascular and extravascular remodeling and inflammation that enhances antigen sensitization and is crucial in adaptive TH2 inflammation. VEGF regulation may be therapeutic in asthma and other TH2 disorders.
doi:10.1038/nm1105
PMCID: PMC3434232  PMID: 15378055
3.  Lung vascular endothelial growth factor expression induces local myeloid dendritic cell activation 
Clinical immunology (Orlando, Fla.)  2009;132(3):371-384.
We previously demonstrated that vascular endothelial growth factor (VEGF) expression in the murine lung increases local CD11c+ MHCII+ DC number and activation. In this study, employing a multicolor flow cytometry, we report increases in both myeloid (mDC) and plasmacytoid (pDC) DC in the lungs of VEGF transgenic (tg) compared to WT mice. Lung pDC from VEGF tg mice exhibited higher levels of activation with increased expression of MHCII and costimulatory molecules. As VEGF tg mice display an asthma-like phenotype and lung mDC play a critical role in asthmatic setting, studies were undertaken to further characterize murine lung mDC. Evaluations of sorted mDC from VEGF tg lungs demonstrated a selective upregulation of cathepsin K, MMP-8, -9, -12, and -14, and chemokine receptors as compared to those obtained from WT control mice. They also had increased VEGFR2 but downregulated VEGFR1 expression. Analysis of chemokine and regulatory cytokine expression in these cells showed an upregulation of macrophage chemotactic protein-3 (MCP-3), thymus-expressed chemokine (TECK), secondary lymphoid organ chemokine (SLC), macrophage-derived chemokine (MDC), IL-1β, IL-6, IL-12 and IL-13. The antigen (Ag) OVA-FITC uptake by lung DC and the migration of Ag-loaded DC to local lymph nodes were significantly increased in VEGF tg mice compared to WT mice. Thus, VEGF may predispose the lung to inflammation and/or repair by activating local DC. It regulates lung mDC expression of innate immunity effector molecules. The data presented here demonstrate how lung VEGF expression functionally affects local mDC for the transition from the innate response to a Th2-type inflammatory response.
doi:10.1016/j.clim.2009.05.016
PMCID: PMC2780370  PMID: 19553159
Rodent; lung; inflammation; dendritic cells; cell activation
4.  Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13–induced tissue responses and apoptosis 
The Journal of Experimental Medicine  2009;206(5):1149-1166.
Mouse breast regression protein 39 (BRP-39; Chi3l1) and its human homologue YKL-40 are chitinase-like proteins that lack chitinase activity. Although YKL-40 is expressed in exaggerated quantities and correlates with disease activity in asthma and many other disorders, the biological properties of BRP-39/YKL-40 have only been rudimentarily defined. We describe the generation and characterization of BRP-39−/− mice, YKL-40 transgenic mice, and mice that lack BRP-39 and produce YKL-40 only in their pulmonary epithelium. Studies of these mice demonstrated that BRP-39−/− animals have markedly diminished antigen-induced Th2 responses and that epithelial YKL-40 rescues the Th2 responses in these animals. The ability of interleukin13 to induce tissue inflammation and fibrosis was also markedly diminished in the absence of BRP-39. Mechanistic investigations demonstrated that BRP-39 and YKL-40 play an essential role in antigen sensitization and immunoglobulin E induction, stimulate dendritic cell accumulation and activation, and induce alternative macrophage activation. These proteins also inhibit inflammatory cell apoptosis/cell death while inhibiting Fas expression, activating protein kinase B/AKT, and inducing Faim 3. These studies establish novel regulatory roles for BRP-39/YKL-40 in the initiation and effector phases of Th2 inflammation and remodeling and suggest that these proteins are therapeutic targets in Th2- and macrophage-mediated disorders.
doi:10.1084/jem.20081271
PMCID: PMC2715037  PMID: 19414556

Results 1-4 (4)