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A more recent version of this article appeared on September 1, 2007

Published online before print July 13, 2007
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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.061122

Accepted for publication May 16, 2007.

Article

Mononuclear Phagocyte-Derived Interleukin-10 Suppresses the Innate Pulmonary Granuloma Cytokine Response in Aged Mice

Bo-Chin Chiu*, Valerie R. Stolberg{dagger}, Christine M. Freeman*, and Stephen W. Chensue*{dagger}@

From the Department of Pathology,* University of Michigan Medical School, Ann Arbor; and the Department of Pathology and Laboratory Medicine,{dagger} Veterans Administration Ann Arbor Healthcare System, Ann Arbor, Michigan

@ To whom correspondence should be addressed. E-mail: schensue{at}med.umich.edu.


  Abstract

Granulomas are sequestration responses observed in a wide variety of clinical conditions, including mycobacterial infection. We previously reported impaired adaptive, Th1 cell-mediated pulmonary granuloma formation in response to bead-immobilized Mycobacterium bovis-purified protein derivative in aged mice. To reveal determinants of age-related immune deficits, the present study examined the effect of aging on early innate stage pulmonary granuloma formation. Aged mice formed more neutrophil-rich innate granulomas with augmented CXCL2 expression followed by a pattern of rapid decay of tumor necrosis factor-{alpha}, interleukin (IL)-6, CCL3, and CXCL2. This was associated with enhanced IL-10 expression. Blockade of IL-10 signaling with anti-IL-10 receptor antibody reversed the age-related decay. Intracellular flow cytometric analysis revealed that CD11b+Gr-1+/- mononuclear phagocytes were the primary leukocyte sources of IL-10 in lungs, and their numbers were increased in aged mice. When exposed to purified protein derivative in vitro, young and old CD11b+Gr-1+/- mononuclear phagocytes from blood or lung had comparable IL-10 expression, suggesting in vivo signals in the aged environment enhanced the number of IL-10-producing cells in the aged lung. Our findings reveal a novel mechanism of age-associated IL-10 mediated pulmonary immune suppression with the potential to alter downstream adaptive immunity.




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Copyright © 2007 by the American Society for Investigative Pathology.