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J. Biol. Chem., Vol. 281, Issue 18, 12277-12288, May 5, 2006

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Anion Channels, Including ClC-3, Are Required for Normal Neutrophil Oxidative Function, Phagocytosis, and Transendothelial Migration^*

Jessica G. Moreland^¶1, A. Paige Davis^¶, Gail Bailey^¶, William M. Nauseef^¶||, and Fred. S. Lamb

From the Division of Critical Care, Department of Pediatrics, The Inflammation Program, ^||Department of Medicine, The University of Iowa, and the ^¶Veterans Affairs Medical Center, Iowa City, Iowa, 52242

NADPH oxidase activity, phagocytosis, and cell migration are essential functions of polymorphonuclear leukocytes (PMNs) in host defense. The cytoskeletal reorganization necessary to perform these functions has been extensively studied, but the role of cell volume regulation, which is likely dependent upon anion channels, has not been defined. Mice lacking the anion channel ClC-3 (Clcn3^(–/–)) died from presumed sepsis following intravascular catheter placement, whereas Clcn3^(+/+) littermates survived. We hypothesized that ClC-3 has a critical role in host defense and reasoned that PMN function would be compromised in these mice. Clcn3^(–/–) PMNs displayed markedly reduced NADPH oxidase activity in response to opsonized zymosan and modestly reduced activity after phorbol 12-myristate 13-acetate. Human PMNs treated with the anion channel inhibitors niflumic acid or 5-nitro-2-(3-phenylpropylamino)benzoic acid had a very similar defect. ClC-3 protein was detected in the secretory vesicles and secondary granules of resting PMNs and was up-regulated to the phagosomal membrane. Clcn3^(–/–) PMNs and human PMNs lacking normal anion channel function both exhibited reduced uptake of opsonized zymosan at 1, 5, and 10 min in a synchronized phagocytosis assay. Niflumic acid-treated PMNs also had impaired transendothelial migration in vitro, whereas migration in vivo was not altered in Clcn3^(–/–) PMNs. Selective inhibition of the swelling-activated chloride channel with tamoxifen profoundly reduced PMN migration but had no effect on NADPH oxidase activity. In summary, PMNs lacking normal anion channel function exhibited reduced NADPH oxidase activity, diminished phagocytosis, and impaired migration. ClC-3 was specifically involved in the respiratory burst and phagocytosis.

Received for publication, October 11, 2005 , and in revised form, March 3, 2006.

^* This work was supported by National Institutes of Health Grants ES00378 (to J. G. M.), HL-62483 (to F. S. L.), T32 HD041922 (to A. P. D.), and AI34879 (to W. M. N.). 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 To whom correspondence should be addressed: Division of Pediatric Critical Care, Dept. of Pediatrics, The University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242. Tel.: 319-356-1615; Fax: 319-353-8597; E-mail: jessica-moreland{at}uiowa.edu.

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