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J. Biol. Chem., Vol. 279, Issue 18, 19113-19121, April 30, 2004

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Cytosolic Phospholipase A₂ Translocates to Forming Phagosomes during Phagocytosis of Zymosan in Macrophages^*

Milena Girotti, John H. Evans, Danielle Burke, and Christina C. Leslie¶||

From the Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, the ^¶Departments of Pathology and Pharmacology, University of Colorado School of Medicine, Denver, Colorado 80206, and the Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309

Resident tissue macrophages mediate early innate immune responses to microbial infection. Cytosolic phospholipase A₂ (cPLA₂) is activated in macrophages during phagocytosis of non-opsonized yeast (zymosan) triggering arachidonic acid release and eicosanoid production. cPLA₂ translocates from cytosol to membrane in response to intracellular calcium concentration ([Ca²⁺]_i) increases. Enhanced green fluorescent protein (EGFP)-cPLA₂ translocated to forming phagosomes, surrounding the zymosan particle by 5 min and completely overlapping with early endosome (Rab5) and plasma membrane (F4/80) markers but only partially overlapping with resident endoplasmic reticulum proteins (GRP78 and cyclooxygenase 2). EGFP-cPLA₂ also localized to membrane ruffles during phagocytosis. Zymosan induced an initial high amplitude calcium transient that preceded particle uptake followed by a low amplitude sustained calcium increase. Both phases were required for optimal phagocytosis. Extracellular calcium chelation prevented only the sustained phase but allowed a limited number of phagocytic events, which were accompanied by translocation of cPLA₂ to the phagosome although [Ca²⁺]_i remained at resting levels. The results demonstrate that cPLA₂ targets the phagosome membrane, which may serve as a source of arachidonic acid for eicosanoid production.

Received for publication, December 18, 2003 , and in revised form, February 7, 2004.

^* This work was supported by National Institutes of Health Grants HL34303 and HL61378. 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplementary Fig. 1 and videos 1-3.

^|| To whom correspondence should be addressed: Dept. of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. Tel.: 303-398-1214; Fax: 303-270-2155; E-mail: lesliec{at}njc.org.

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