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J. Biol. Chem., Vol. 281, Issue 17, 11949-11954, April 28, 2006

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Cytokine Secretion via Cholesterol-rich Lipid Raft-associated SNAREs at the Phagocytic Cup^*

From the Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia

Lipopolysaccharide-activated macrophages rapidly synthesize and secrete tumor necrosis factor (TNF) to prime the immune system. Surface delivery of membrane carrying newly synthesized TNF is controlled and limited by the level of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins syntaxin 4 and SNAP-23. Many functions in immune cells are coordinated from lipid rafts in the plasma membrane, and we investigated a possible role for lipid rafts in TNF trafficking and secretion. TNF surface delivery and secretion were found to be cholesterol-dependent. Upon macrophage activation, syntaxin 4 was recruited to cholesterol-dependent lipid rafts, whereas its regulatory protein, Munc18c, was excluded from the rafts. Syntaxin 4 in activated macrophages localized to discrete cholesterol-dependent puncta on the plasma membrane, particularly on filopodia. Imaging the early stages of TNF surface distribution revealed these puncta to be the initial points of TNF delivery. During the early stages of phagocytosis, syntaxin 4 was recruited to the phagocytic cup in a cholesterol-dependent manner. Insertion of VAMP3-positive recycling endosome membrane is required for efficient ingestion of a pathogen. Without this recruitment of syntaxin 4, it is not incorporated into the plasma membrane, and phagocytosis is greatly reduced. Thus, relocation of syntaxin 4 into lipid rafts in macrophages is a critical and rate-limiting step in initiating an effective immune response.

Received for publication, January 27, 2006 , and in revised form, March 2, 2006.

^* This work was supported by a grant from the National Institutes of Health and by a fellowship and a grant (to J. L. S.) from the National Health and Medical Research Council of Australia. 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: Institute for Molecular Biosciences, the University of Queensland, Brisbane, Queensland 4072, Australia. Tel.: 61-7-3346-2034; Fax: 61-7-3346-2101; E-mail: j.stow{at}imb.uq.edu.au.

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