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Group V Secretory Phospholipase A₂ Modulates Phagosome Maturation and Regulates the Innate Immune Response against Candida albicans ¹

Barbara Balestrieri^*,2, Akiko Maekawa^*, Wei Xing^*, Michael H. Gelb, Howard R. Katz^* and Jonathan P. Arm^*,

^* Department of Medicine, Harvard Medical School, and Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Boston, MA 02115; Departments of Chemistry and Biochemistry, University of Washington, Seattle, WA 98195; and Partners Asthma Center, Brigham and Women’s Hospital, Boston, MA 02115

Phospholipase A₂ (PLA₂) hydrolyzes the sn-2 position of cell membrane phospholipids to release fatty acids and lysophospholipids. We have previously reported that group V secretory PLA₂ (sPLA₂) translocates from the Golgi and recycling endosomes of mouse peritoneal macrophages to newly formed phagosomes and regulates the phagocytosis of zymosan, suggesting a role in innate immunity. Here we report that in macrophages lacking group V sPLA₂, phagosome maturation was reduced 50–60% at early time points while the binding of zymosan was unimpaired. The ability of group V sPLA₂ to regulate phagocytosis extended to phagocytosis of IgG- and complement-opsonized sheep RBC. Moreover, macrophages lacking group V sPLA₂ had delays in phagocytosis, phagosome maturation, and killing of Candida albicans. Cytokine production and eicosanoid generation were not impaired by the lack of group V sPLA₂. Furthermore, in a model of systemic candidiasis, mice lacking group V sPLA₂ had an increased fungal burden in the kidney, liver, and spleen at day 7 postinfection and increased mortality. Thus, group V sPLA₂ regulates phagocytosis through major phagocytic receptors and contributes to the innate immune response against C. albicans by regulating phagocytosis and killing through a mechanism that is likely dependent on phagolysosome fusion.

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¹ This work was supported by Grant AI064226 from the National Institute of Allergy and Infectious Diseases (to B.B.); by bridge grants from the American Academy of Allergy, Asthma and Immunology and the Brigham and Women’s Hospital Biomedical Research Institute; and by National Institutes of Health Grants HL070946 and HL036110 (to J.P.A.), AI041144 and HL036110 (to H.R.K.), and R37HL36235 (to M.H.G.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.

² Address correspondence and reprint request to Dr. Barbara Balestrieri, Brigham and Women’s Hospital, Smith Research Building, Room 614A, 1, Jimmy Fund Way, Boston, MA 02115. E-mail address: bbalestrieri{at}rics.bwh.harvard.edu

³ Abbreviations used in this paper: ROS, reactive oxygen species; PLA₂, phospholipase A₂; cPLA₂, cytosolic phospholipase A₂; sPLA₂, secretory phospholipase A₂; sRBC, sheep RBC; Pla2g5, the gene encoding group V sPLA₂; ppc, particles per cell; moi, multiplicity of infection; Cys-LT, cysteinyl leukotriene.