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Nonclassical IL-1 Secretion Stimulated by P2X7 Receptors Is Dependent on Inflammasome Activation and Correlated with Exosome Release in Murine Macrophages¹

Yan Qu, Luigi Franchi, Gabriel Nunez and George R. Dubyak^2,*,

^* Department of Physiology and Biophysics and Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH 44120; and Department of Pathology, University of Michigan, Ann Arbor, MI 48109

Several mechanistically distinct models of nonclassical secretion, including exocytosis of secretory lysosomes, shedding of plasma membrane microvesicles, and direct efflux through plasma membrane transporters, have been proposed to explain the rapid export of caspase-1-processed IL-1 from monocytes/macrophages in response to activation of P2X7 receptors (P2X7R) by extracellular ATP. We compared the contribution of these mechanisms to P2X7R-stimulated IL-1 secretion in primary bone marrow-derived macrophages isolated from wild-type, P2X7R knockout, or apoptosis-associated speck-like protein containing a C-terminal CARD knockout mice. Our experiments revealed the following: 1) a novel correlation between IL-1 secretion and the release of the MHC-II membrane protein, which is a marker of plasma membranes, recycling endosomes, multivesicular bodies, and released exosomes; 2) a common and absolute requirement for inflammasome assembly and active caspase-1 in triggering the cotemporal export of IL-1 and MHC-II; and 3) mechanistic dissociation of IL-1 export from either secretory lysosome exocytosis or plasma membrane microvesicle shedding on the basis of different requirements for extracellular Ca²⁺ and differential sensitivity to pharmacological agents that block activation of caspase-1 inflammasomes. Thus, neither secretory lysosome exocytosis nor microvesicle shedding models constitute the major pathways for nonclassical IL-1 secretion from ATP-stimulated murine macrophages. Our findings suggest an alternative model of IL-1 release that may involve the P2X7R-induced formation of multivesicular bodies that contain exosomes with entrapped IL-1, caspase-1, and other inflammasome components.

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 by National Institutes of Health Grants GM36387 (to G.R.D.) and AI063331/AI064748 (to G.N.).

² Address correspondence and reprint requests to Dr. George R. Dubyak, Department of Physiology and Biophysics, Case Western Reserve University School of Medicine,10900 Euclid Avenue, Cleveland, OH 44120. E-mail address: george.dubyak{at}case.edu

³ Abbreviations used in this paper: PAMP, pathogen-associated molecular pattern; AMC, aminomethylcoumarin; BEL, bromoenol lactone; BMDM, bone marrow-derived macrophage; BSS, basal saline solution; ASC, apoptosis-associated speck-like protein containing a C-terminal CARD; NOD, nucleoside oligomerization domain; NALP, Nacht, LRR, and PYRIN domain containing proteins; LAMP, lysosome-associated membrane protein; MVB, multivesicular body; P2X7R, P2X7 receptor; Px1, pannexin-1.

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