Hong Du, Ph.D.
Dr. Du’s laboratory focuses on the molecular mechanisms that connect lipid metabolism to chronic inflammation and pathogenesis.
Professor of Pathology and Laboratory Medicine
Member of IU Simon Cancer Center
Campus Address: MS A132
- B.Sc., 1982: Wuhan University, Virology, Wuhan, China
- Ph.D., 1989: City University of New York, Biochemistry, New York, NY
- Post Doctoral. 1989-1992: The Rockefeller University, Molecular Biology and Biochemistry, New York, NY
Description and Summary of the Research focus of Dr. Du
Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters and triglycerides to generate free fatty acid and cholesterol in the lysosomes of various cells. The down stream metabolites of these compounds serve as ligands for nuclear receptors and transcription factors that regulate gene expression, cell proliferation/differentiation and apoptosis. The physiological roles of LAL are evaluated using a gene targeted mouse model, LAL knock out mice (lal-/-) that created in my laboratory. Further characterization of lal-/- mice demonstrated additional roles of LAL in fat mobilization, insulin resistance, macrophage proliferation, respiratory inflammation and remodeling. Our current research focuses on mechanisms that connect lipid metabolism disorder to the systemic inflammation that leads to multiple forms of pathogenic phenotypes in multiple organs.
1. Abnormal myeloid lineage cell differentiation
Genetic ablation of the LAL gene has resulted in a systemic increase of myeloid lineage cells. Aberrant growth and differentiation of myeloid cells in lal-/- mice arises from dysregulated production of progenitor cells in the bone marrow. lal-/- mice display increased numbers of primitive lin-Sca-1+c-Kit+ (LSK) cells and granulocyte-macrophage precursors (GMP). As a consequence, lal-/- mice develop significant myeloid infiltration, particularly with CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) in multiple organs (spleen, thymus, liver, lung, etc.). lal-/- CD11b+Gr-1+ cells display suppressive activity on T cell proliferation and function in vitro. Bone marrow chimeras confirm that the myeloproliferative disorder in lal-/- mice is primarily due to autonomous defects in myeloid progenitor cells. When LAL is reintroduced into lal-/- mice by myeloid-specific doxycycline-inducible transgenic system, expression of hLAL in myeloid cells reverses abnormal myelopoiesis in the bone marrow starting at the GMP stage and reduces systemic expansion of MDSCs. Myeloid cell LAL expression also improves the proliferation and function of peripheral T cells. In vitro co-culture experiments show that myeloid hLAL expression in lal-/- mice reverses CD11b+GR-1+ myeloid cell suppression of T cell proliferation, T cell signaling activation, and lymphokine secretion. Blocking Stat3 and NFkB p65 signaling by small molecule inhibitors in MDSCs also achieves the similar effect. Injection of anti-Gr-1 antibody into lal-/- mice to deplete MDSCs restores T cell proliferation. LAL in myeloid cells plays a critical role in maintaining normal hematopietic cell development and balancing immunosuppression and inflammation.
2. Abnormal T cell lineage cell differentiation
In lal-/- mice, blockage of cholesteryl ester and triglyceride metabolism leads to abnormal organization of the thymus and spleen, and neutral lipid accumulation in these organs. LAL deficiency impairs progression of T cell development in the thymus. Peripheral T cells are dramatically reduced in lal-/- mice. This is largely due to increased apoptosis and decreased proliferation of lal-/- T cells in thymus and peripheral compartments. lal-/- T cells loss ability in responding to T cell receptor (TCR) stimulation, including reduced expression of cell surface receptor, abolishment of T cell proliferation, the decreased expression of T lymphokines after stimulation by anti-CD3 plus anti-CD28, or phorbol-12-myristate-13-acetate (PMA) and Ionomycin. Differentiation of Th1 and Th2 CD4+ effector lymphocytes by TCR stimulation is blocked in lal-/- mice. Bone marrow chimeras demonstrate retardation of T cell development and maturation in lal-/- mice due to the defects in T cell precursors. Therefore, LAL plays essential roles in development, homeostasis and function of T cells.
3. LAL downstream gene and tumorigenesis
Affymetrix GeneChip analysis identified a group of abnormally expressed genes in lal-/- mice. Overexpression of LAL negatively-regulated downstream genes (MMP12 and Api6) or a dominant negative form of its downstream effector peroxisome proliferator-activated receptor-g (PPARg) in myeloid-specific doxycycline-inducible bitransgenic mouse models abnormally elevates frequencies and total numbers of LK, LSK, CMP and GMP progenitor populations in the bone marrow. As a result, MDSCs are systemically increased in association with activation of Stat3, NF-kB, Erk1/2 and p38 molecules. MDSCs inhibit the proliferation and lymphokine production of T cells both in vivo and in vitro. Multiple forms of carcinoma and sarcoma in the lung, liver, spleen and lymph nodes are observed in these mice of LAL downstream genes or effectors. Bone marrow transplantation reveals that a myeloid autonomous defect is responsible for MDSC expansion, immunosuppression and tumorigenesis.
Wu, L.Y., Yan, C., Czader, M.B., Foreman, O., and Du, H. (2011) Inhibition of peroxisome proliferator-activated receptor-g in myeloid lineage cells induces systemic inflammation, immunosuppression and tumorigenesis. Blood, In press.
Wu, L.Y, Wang, G.X., Qu, P., Yan, C., and Du, H. (2011) Overexpression of Dominant Negative Peroxisome Proliferator-Activated Receptor-gamma (PPARg) in Alveolar Type II Epithelial Cells Causes Inflammation and T-Cell Suppression in the Lung. Am. J. Pathol. 178: 2191-2204.
Qu, P., Yan, C., and Du, H. (2011) Matrix Metalloproteinase 12 overexpression in myeloid lineage cells plays a key role in modulating hepatopoiesis, myelopoiesis, immune suppression and lung tumorigenesis. Blood. 117: 4476-4489.
Li, Y., Qu, P., Wu, L.Y., Li, B. L., Du, H., and Yan, C. (2011) Api6/AIM/Spa overexpression in alveolar type II epithelial cells induces spontaneous lung adenocarcinoma. Cancer Res. 71:5488-5499.
Wu, L.Y., Du, H., Li, Y., Qu, P., and Yan, C (2011) Signal Transducers and activators of the transcription3 promotes myeloid derived suppressor cell expansion and immune suppression during lung tumorigenesis. Am. J. Pathol. 179:2131-2141.
Bowden, K.L., Bilbey, N. J., Bilawchuk, L.M., Boadu, E., Ory, D.S., Hegele, R.A., Du, H., Chan, T., and Francis, G.A. (2011) Lysosomal acid lipase deficiency impairs regulation of ABCA1 and formation of high density lipoproteins in cholesteryl ester storage disease. J. Biol. Chem. 286:30624-30635.
Qu, P., Yan, C., Blum, J. S., Kapur, R., and Du, H. (2011) Myeloid-specific expression of human lysosomal acid lipase corrects malformation and malfunction of myeloid-derived suppressive cells in lal-/- mice. J. Immunol. 187:3854-3866.
Qu, P., Shelley, W.C., Yoder, M.C., Wu, L. Y., Du, H., and Yan, C. (2010) Critical Roles of Lysosomal Acid Lipase in Myelopoiesis. Am. J. Pathol.176: 2394-2404.
Qu, P., Roberts., Li, Y., Du, H., and Yan, C. (2009) Myeloid expression of Api6/AIM/Spa induce systemic inflammation and adenocarcinoma in the lung. J. Immunol. 182:1648-1659.
Qu, P., Roberts, J., Li, Y., Albrecht, M., Cummings, O.W., Eble, J.N., Du, H., and Yan, C., (2009) Stat3 downstream genes serve as biomarkers in human lung carcinomas and chronic pulmonary disease. Lung Cancer 63: 341-347.
Rosenbaum, A I., Rujoi, M., Huang, A. Y., Du, H., Grabowski, G.A., Maxfield, F.R. (2009) Chemical screen to reduce sterol accumulation in Niemann-Pick C disease cells identifies novel lysosomal acid lipase inhibitors. Biochim. Biophys. Acta. 1791: 1155-1165.
Qu, P., Du, H., Wang, X., and Yan, C. (2009) Matrix Metalloproteinase 12 overexpression in lung epithelial cells plays a key role in emphysema to lung brochioalveolar adenocarcinoma transition. Cancer Res. 69: 7252-7261.
Du, H., Cameron, T.C., Garger, S.J., Pogue, G.P., Hamm, L.A., White, E., Hanley, K.M., and Grabowski, G.A. (2008) Wolman disease/cholesteryl ester storage disease: efficacy of plant-produced human lysosomal acid lipase in mice. J. Lipid Res. 49:1646-1657.
Qu, P., Du, H., Wilkes, D.S., and Yan, C. (2008) Critical Roles of neutral lipid in T cell development, homeostasis and function. Am. J. Pathology. 174: 944-956.
Li, Y., Qin, Y., Li, H., Wu, R.L., Yan, C., and Du, H. (2007) Lysosomal acid lipase overexpression disrupts lamellar body genesis and alveolar structure in the lung. International J. Experimental Pathology. 88:427-436.
Yan, C., Lian, X., Dai, Y., Qin, Y., White, A., Akinbi, H., Wang, X., and Du, H. (2007) Gene delivery by hSP-B promoter in lung alveolar type II epithelial cells in LAL knock out mice through bone marrow mesenchymal stem cells. Gene Therapy. 14:1461-1470.
Li, Y., Du, H., Qin, Y.L., Roberts, J., Cummings, O.W., and Yan, C. (2007) Activation of the signal transducers and activators of transcription 3 pathway in alveolar epithelial cells induces inflammation and adenocarcinomas in mouse lung. Cancer Research. 67:8494-8503.
Wu, D.F., Sharan, C., Yang, H., Goodwin, S.J., Zhou, L., Grabowski, G.A., Du, H., and Guo, Z.M. (2007) Apolipoprotein E-deficient lipoproteins induce foam cell formation by down regulation of lysosomal hydrolases in macrophages. J. Lipid Res. 48:2571-2578.