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* Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil;
Departamento de Imunologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; and
Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
Lipid bodies (also known as lipid droplets) are emerging as inflammatory organelles with roles in the innate immune response to infections and inflammatory processes. In this study, we identified MCP-1 as a key endogenous mediator of lipid body biogenesis in infection-driven inflammatory disorders and we described the cellular mechanisms and signaling pathways involved in the ability of MCP-1 to regulate the biogenesis and leukotriene B4 (LTB4) synthetic function of lipid bodies. In vivo assays in MCP-1–/– mice revealed that endogenous MCP-1 produced during polymicrobial infection or LPS-driven inflammatory responses has a critical role on the activation of lipid body-assembling machinery, as well as on empowering enzymatically these newly formed lipid bodies with LTB4 synthetic function within macrophages. MCP-1 triggered directly the rapid biogenesis of distinctive LTB4-synthesizing lipid bodies via CCR2-driven ERK- and PI3K-dependent intracellular signaling in in vitro-stimulated macrophages. Disturbance of microtubule organization by microtubule-active drugs demonstrated that MCP-1-induced lipid body biogenesis also signals through a pathway dependent on microtubular dynamics. Besides biogenic process, microtubules control LTB4-synthesizing function of MCP-1-elicited lipid bodies, in part by regulating the compartmentalization of key proteins, as adipose differentiation-related protein and 5-lipoxygenase. Therefore, infection-elicited MCP-1, besides its known CCR2-driven chemotactic function, appears as a key activator of lipid body biogenic and functional machineries, signaling through a microtubule-dependent manner.
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1 This work was supported by Howard Hughes Medical Institute (to P.T.B.), PRONEX-MCT, Conselho Nacional de Pesquisa (Brazil), and Fundação de Amparo à Pesquisa do Rio de Janeiro.
2 Address correspondence and reprint requests to Dr. Patricia T. Bozza, Laboratório de Imunofarmacologia, Departamento de Fisiologia e Farmacodinâmica, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenuda Brasil 4365, Manguinhos, Rio de Janeiro, RJ, Brazil 21045-900. E-mail address: pbozza{at}ioc.fiocruz.br or Dr. Christianne Bandeira-Melo, Laboratório de Inflamação, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil 21941-902. E-mail address: cbmelo{at}biof.ufrj.br
3 Abbreviations used in this paper: ER, endoplasmic reticulum; ADRP, adipose differentiation related protein; LDL, low-density lipoprotein; oxLDL, oxidized LDL; 5-LO, 5-lipoxygenase; LTB4, leukotriene B4; CLP, cecum ligation and puncture; EDAC, 1-ethyl-3 (3-dimethylamino-propyl) carbodiimide.
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