John J. Osterholzer,
Internal Medicine, Pulmonary and Critical Care Division
Research in my laboratory is focused on elucidating the role of lung dendritic cells (DC) in orchestrating adaptive immune responses in the lungs in response to infectious or inflammatory stimuli. We utilize murine models of fungal infection (primarily Cryptococcus neoformans) or lung epithelial cell injury, to study mechanisms of DC recruitment, differentiation, activation, and their ability to influence T cell polarization within the lung microenvironment. In parallel, we also investigate the origin and functions of pulmonary monocytes and macrophage populations as cell types which also link innate and adaptive immune responses. Ongoing studies continue to explore the mechanistic attributes of these cells (antigen presentation, fungicidal capacity, profibrotic potential) and investigate whether enhancing or diminishing the accumulation of these cells further alters the resultant immune and/or fibrotic response following infection or lung injury. Experimental techniques used in these investigations include (but are not limited to): 1) animal modeling; 2) small animal surgery (intratracheal, intra-peritoneal, and intravenous injection; organ removal and tissue preparation), 3) 8-10 parameter multi-color flow cytometric analysis; 4) real time RT-PCR; 5) cytokine and chemokine quantification (by ELISA and Luminex); 6) cell culture and in vitro cell differentiation and activation; 7) histology; 8) immunohistochemistry; and 9) laser capture micro-dissection and confocal fluorescent microscopy. Opportunities to create and use transgenic mice to help answer specific scientific questions relevant to these studies are being explored.
Representative Recent Publications
He, X. Lyons, DM. Toffaletta, DL. Wang. F. Qui, Y. Davis, MJ. Meister, DL. Dayrit, JK. Lee, A. Osterholzer, JJ. Perfect, JR. and Olszewski, MA. “Cryptococcal Virulence Factors Identified by Screening of Mutants in vitro Exhibit Differential Potentials for Pulmonary Virulence and CNS Dissemination by Modulating Adaptive Immune Responses. The American Journal of Pathology, “Accepted article” June 2012, in press.
Serazani, CH. Cane, S. Collins, A. Morato-Marques, M. Osterholzer, JJ. and Peters-Golden, M. “Macrophage dectin-1 expression is controlled by leukotriene B4 via a GM-CSF/PU.1 axis”. The Journal of Immunology “Accepted Article” Epub June 13, 2012.
Osterholzer, JJ. Christensen, P.J. Lama, V. Horowitz, J.C. Hattori, N. Subbotina, N. Cunningham, A. Lin, Y. Murdock, B.J. Morey, R.E. Olszewski, M.A. Lawrence, D.A. Simon, R.H. and Sisson, T.H. “PAI-1 Promotes the Accumulation of Exudate Macrophages and Worsens Pulmonary Fibrosis Following Type II Alveolar Epithelial Cell Injury”. The Journal of Pathology "Accepted Article"; DOI: 10.1002/path.3992; Epub Jan 19, 2012.
Qiu, Y. Zeltz, S. Zhang, Y. Wang, F. Chen, G-H. Murdock, B.J. Dayearit, J. Bhan, U. Toews, G.B. Osterholzer, JJ. Standiford, T.J. and Olszewski, M.A. “Early induction of CCL7 downstream of TLR9 signaling promotes the development of robust immunity to cryptococcal infection”. The Journal of Immunology, 188(8):3940-8. 2012.
Murdock BJ, Shreiner AB, McDonald RA, Osterholzer JJ, White ES, Toews GB, Huffnagle GB. Co-evolution of TH1, TH2 and TH17 Responses During Repeated Pulmonary Exposure to Aspergillus fumigatus Conidia. Infection and Immunity, 79(1):125-35, 2011.
Osterholzer, JJ. Chen, GH. Olszewski, MA. Zhang, YM. Curtis, JL. Huffnagle, GB. and Toews, GB. “CCR2-mediated accumulation of fungicidal exudate macrophages in mice which clear cryptococcal lung infection”. American Journal of Pathology, 178(1): 198-211, 2011.
Chen, GH. Osterholzer, JJ (co-1st author). Choe, MY. McDonald, RA. Olszewski, MA. Huffnagle, GB. and Toews, GB. “Dual roles of CD40 on microbial containment and the development of immunopathology in response to persistent fungal infection in the lung”. American Journal of Pathology, 177 (11): 2459-2471, 2010.
Osterholzer, JJ. Chen, GH. Olszewski, MA. Curtis, JL. Huffnagle, GB, and Toews, GB. “Accumulation of CD11b+ lung dendritic cells in response to fungal infection results from the CCR2-mediated recruitment and differentiation of Ly6C(high) monocytes”. Journal of Immunology, 183(12):8044-53, 2009.
Jain AV, Zhang Y, Fields WB, McNamara DA, Choe MY, Chen GH, Erb-Downward J, Osterholzer JJ, Toews GB, Huffnagle GB, and Olszewski MA. “Th2 but not Th1 Immune Bias Results in Altered Lung Functions in Murine Model of Pulmonary Cryptococcus neoformans Infection”. Infection and Immunity, 77(12):5389-5399, 2009.
Osterholzer, JJ, Milam, JE, Chen, GH, Toews, GB, Huffnagle, GB, and Olszewski, MA. “The role of dendritic cells and alveolar macrophages in regulating early host defense against pulmonary infection with Cryptococcus neoformans”. Infection and Immunity, 77(9):3749-58, 2009.
Osterholzer, JJ. Suran, R. Milam, JE. Montano, GT. Chen, GH. Sonstein, J. Curtis, JL. Huffnagle, GB, Toews, GB. and Olszewski, MA. “Cryptococcal urease promotes the accumulation of immature dendritic cells and a non-protective T2 immune response within the lung”. American Journal of Pathology, 174(3):932-43, 2009.
Curtis, JL. Todt, JC. Hu, B. Osterholzer, JJ. And Freeman, CM. “The contribution of Tyro3 family receptor tyrosine kinases to the heterogeneity of apoptotic cell uptake by mononuclear phagocytes”. Frontiers in Bioscience, 1431: 2631- 2646, 2009.
Osterholzer, JJ. Curtis, JL. Polak, T. Ames, T. Chen, GH. McDonald, R. Huffnagle, GB, and Toews, GB. “CCR2 mediates conventional dendritic cell recruitment and the formation of bronchovascular mononuclear cell infiltrates in the lungs of mice infected with Cryptococcus neoformans”. Journal of Immunology 181: 610-620, 2008.
Bhan, U. Lukacs, NW. Osterholzer, JJ. Newsteadt, MW. Zeng, X. Moore, TA. McMilan, TR. Krieg, AM. Akira, S. and Standiford, TJ. “TLR9 is required for protective innate immunity in gram-negative bacterial pneumonia: role of dendritic cells”. Journal of Immunology 179(6):3937-46, 2007.
Osterholzer, JJ. Sonstein, J. Polak, T. Allen, T. Moore, BB. Chensue, SW. Toews, GB. and Curtis, JL. “CCR2 and CCR6 mediate the accumulation of immature dendritic cells within the lungs of mice in response to particulate antigen.” Journal of Immunology, 175:874-883, 2005.