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Gr-1^high Polymorphonuclear Leukocytes and NK Cells Act via IL-15 to Clear Intracellular Haemophilus influenzae in Experimental Murine Peritonitis and Pneumonia¹

Shuichi Miyazaki^2,*, Fumio Ishikawa, Kayo Shimizu, Tsuneyuki Ubagai, Paul H. Edelstein^¶ and Keizo Yamaguchi^*

^* Departments of Microbiology and Infectious Disease, School of Medicine, Toho University, Tokyo, Japan; Department of Immunology, School of Medicine, Toho University, Tokyo, Japan; Kaken Geneqs, Chiba, Japan; Department of Microbiology and Immunology, School of Medicine, Teikyo University, Tokyo, Japan; and ^¶ Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104

Polymorphonuclear leukocytes (PMNs) can be divided into Gr-1^high and Gr-1^low subpopulations, but the differences in the functions of these cells in the host are unknown. This study investigated the roles of these two cell populations in the clearance of an intracellular pathogen (Haemophilus influenzae) causing murine peritonitis and pneumonia. Microarray analysis and quantitative real-time PCR analysis of proteose peptone-elicited peritoneal murine PMNs showed that IL-15 mRNA levels were significantly higher in Gr-1^high PMNs than in Gr-1^low PMNs. In addition, IL-15 was produced only by Gr-1-positive PMNs, especially Gr-1^high PMNs. IL-15 was required for efficient clearance of experimental murine H. influenzae pneumonia, as 4 days postinfection lungs from IL-15 knockout mice contained 50- to 100-fold more bacteria than did wild-type mouse lungs. Gr-1 PMN-depleted C57BL/6 mice were more susceptible to H. influenzae pneumonia than were Gr-1 PMN replete C57BL/6 mice or C57BL/6 nude mice, demonstrating that Gr-1 PMNs are important in the clearance of intracellular bacteria. IL-15-activated NK cells killed H. influenzae in PMNs. Flow cytometry confirmed the expression of CD69 on the cell membrane of IL-15-activated NK cells. Our results show that Gr-1^high PMNs produce more IL-15 than Gr-1^low PMNs, and that IL-15-activated NK cells protect against early infection by H. influenzae.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry Education, Science, Sports and Culture of Japan (No. 16590373).

² Address correspondence and reprint requests to Asst. Prof. Shuichi Miyazaki, Department of Microbiology and Infectious Disease, School of Medicine, Toho University, Omori-nishi 5-21-16, Ota-ku, Tokyo 143-8540, Japan. E-mail address: shuichi{at}med.toho-u.ac.jp

³ Abbreviations used in this paper: PMN, polymorphonuclear leukocyte; MRSA, methicillin-resistant Staphylococcus aureus; KO, knockout; PEC, peritoneal exudate cell; PP, proteose peptone; CBO, cell-bound organism.

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