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Infection and Immunity, May 2009, p. 1790-1797, Vol. 77, No. 5
0019-9567/09/$08.00+0     doi:10.1128/IAI.01441-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Absence of Hck, Fgr, and Lyn Tyrosine Kinases Augments Lung Innate Immune Responses to Pneumocystis murina

Michael P. Nelson,^1, Allison E. Metz,^1, Shaoguang Li,² Clifford A. Lowell,³ and Chad Steele^1*

Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama,¹ The Jackson Laboratory, Bar Harbor, Maine,² Department of Laboratory Medicine, University of California School of Medicine, San Francisco, California³

Received 24 November 2008/ Returned for modification 8 January 2009/ Accepted 19 February 2009

Src family tyrosine kinases (SFKs) phosphorylate immunotyrosine activation motifs in the cytoplasmic tail of multiple immunoreceptors, leading to the initiation of cellular effector functions, such as phagocytosis, reactive oxygen species production, and cytokine production. SFKs also play important roles in regulating these responses through the activation of immunotyrosine inhibitory motif-containing inhibitory receptors. As myeloid cells preferentially express the SFKs Hck, Fgr, and Lyn, we questioned the role of these kinases in innate immune responses to Pneumocystis murina. Increased phosphorylation of Hck was readily detectable in alveolar macrophages after stimulation with P. murina. We further observed decreased phosphorylation of Lyn on its C-terminal inhibitory tyrosine in P. murina-stimulated alveolar macrophages, indicating that SFKs were activated in alveolar macrophages in response to P. murina. Mice deficient in Hck, Fgr, and Lyn exhibited augmented clearance 3 and 7 days after intratracheal administration of P. murina, which correlated with elevated levels of interleukin 1β (IL-1β), IL-6, CXCL1/KC, CCL2/monocyte chemoattractant protein 1, and granulocyte colony-stimulating factor in lung homogenates and a dramatic increase in macrophage and neutrophil recruitment. Augmented P. murina clearance was also observed in Lyn^–/– mice 3 days postchallenge, although the level was less than that observed in Hck^–/– Fgr^–/– Lyn^–/– mice. A correlate to augmented clearance of P. murina in Hck^–/– Fgr^–/– Lyn^–/– mice was a greater ability of alveolar macrophages from these mice to kill P. murina in vitro, suggesting that SFKs regulate the alveolar macrophage effector function against P. murina. Mice deficient in paired immunoglobulin receptor B (PIR-B), an inhibitory receptor activated by SFKs, did not exhibit enhanced inflammatory responsiveness to or clearance of P. murina. Our results suggest that SFKs regulate innate lung responses to P. murina in a PIR-B-independent manner.

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* Corresponding author. Mailing address: Departments of Medicine and Microbiology, Division of Pulmonary, Allergy and Critical Care Medicine, School of Medicine, University of Alabama—Birmingham, 1900 University Blvd., THT 437A, Birmingham, AL 35294. Phone: (205) 996-9598. Fax: (205) 934-1721. E-mail: chadsteele{at}uab.edu

Published ahead of print on 2 March 2009.

Editor: A. Casadevall

M.P.N and A.E.M. contributed equally to this work.

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Infection and Immunity, May 2009, p. 1790-1797, Vol. 77, No. 5
0019-9567/09/$08.00+0     doi:10.1128/IAI.01441-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.