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John J. Osterholzer, M.D.
Assistant Professor of Internal Medicine,
Pulmonary and Critical Care Division
Veteran Affairs Ann Arbor Healthcare System

Research Interests

Research in my laboratory is focused on elucidating the role of lung dendritic cells (DC), monocytes, and macrophages in orchestrating adaptive immune responses in the lungs in response to infectious or inflammatory stimuli. We primarily utilize murine models of fungal infection (primarily Cryptococcus neoformans), 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. We further explore molecular mechanisms of communication between the lung and bone marrow with a specific interest in the role of chemokine receptor 2 (CCR2) in this process. Our recent findings demonstrate that the failed development of protective T1 immune responses against cryptococcal lung infection results from a dramatic impairment in the accumulation of monocytes-derived DC and exudate macrophages. Ongoing studies will continue to explore the mechanistic attributes of these cells (antigen presentation, fungicidal capacity) and investigate whether enhancing or diminishing the accumulation of these cells further alters the resultant immune response against the organism. In related work, we have also initiated a series of studies invetigating the role of lung monocytes, DC, and macrophages in response to non-infectious lung epithelial cell injury to determine whether (and how) these cells constribute to lung fibrosis.  

Representative Recent Publications

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. PM16002685/PMC2396199

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. PM18566428/PMC2735104

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. PM19218345/PMC2665753

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. PM19564388/PMC2737986

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. PM19933856/NIHMSID 590739/PMC pending

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. PM20864680/PMC2966803

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. PM21224057/PMC3069860

Qiu, Y. Zeltzer, 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. PM22422883/PMC3324623

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, 228(2):170-80, 2012. PM22262246/PMC3529409

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. “Virulence factors identified by Cryptococcus neoformans mutant screen differentially modulate lung immune responses and brain dissemination. The American Journal of Pathology, 181(4):1356-66, 2012. PM22846723/PMC3463625

Qiu, Q. Davis, MJ. Dayrit, JK. Hadd, Z. Meister, DL.
Osterholzer JJ, Willaimson, PR. and Olszewski, MA. “Immune modulation mediated by cryptococcal laccase promotes pulmonary growth and brain dissemination of virulent Cryptococcus neoformans in mice”. PLoS ONE, 7(10) e47853, 2012. PM23110112/PMC3478276

Brumshagen, C. Maus, R. Bischof, A. Ueberberg, B. Bohling, J.
Osterholzer JJ, Ogunniyi, AD. Paton, JC. Welte, T. and Maus, UA. FMS-like tyrosine kinase-3 ligand (Flt3L) treatment of mice aggravates acute lung injury in response to S. pneumoniae: role of pneumolysin”. Infection and Immunity, 80(12):4281-4290, 2012. PM23006850/PMC3497444

Osterholzer JJ, Olszewski, MA. Chen, G-H. Subbotina, N. Browning, K. Lin, Y. Murdock, B.J. Morey, R.E. Simon, R.H. and Sisson, T.H. “Implicating Exudate Macrophages and Ly-6C(high) Monocytes in CCR2-Dependent Lung Fibrosis Following Gene-Targeted Alveolar Injury”. The Journal of Immunology 190(7):3447-57, 2013. PM23467934/PMC3608799

Qiu, Q. MJ. Dayrit, Davis, Carolan, JF.,
Osterholzer JJ, Curtis, JL. and Olszewski, MA. “Scavenger Receptor A Modulates the Immune Response to Pulmonary Cryptococcus neoformans Infection”. The Journal of Immunology, 191(1):238-48, 2013. PM237338/PMC pending

Murdock BJ, Huffnagle GB, Olszewski MA, and
Osterholzer JJ. “Interleukin-17A Enhances Host Defense against Cryptococcal Lung Infection through Effects Mediated by Leukocyte Recruitment, Activation, and Gamma Interferon Production”. Infection and Immunity, 82(3): 937–948, 2014. PM 24324191/PMC3957981


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