Lipid bodies in innate immune response to bacterial and parasite infections
Introduction
Lipid bodies, also termed lipid droplets or adiposomes, are cytoplasmic lipid-rich organelles found in many organisms, including plants, bacteria, yeast, and both non-mammalian and mammalian animal cells [1], [2], [3]. Lipid body structure consists of a neutral core composed by triacylglycerol, cholesterol esters and diacylglycerol surrounded by a half-unit membrane of a complex variety of phospholipids with a unique fatty acid composition [1], [4], [5]. Pertinent to leukocyte functions in inflammation, lipid bodies in different leukocyte types are enriched in arachidonate esterified in phospholipid and neutral lipid [6], [7], [8], [9].
In addition to lipids, lipid bodies compartmentalize a diverse set of proteins. The major structural proteins present at the surface of lipid bodies are the proteins from the PAT family, named adipose differentiation related protein (ADRP, adipophilin), perilipin and TIP 47 (tail-interacting protein of 47 kDa). These proteins have been implicated in the lipid body assembling and biogenesis [10], [11], [12], [13]. Notably, lipid bodies compartmentalize enzymes involved in the biosynthesis and catabolism of lipids [9], [14], [15], [16], [17], [18]; caveolin and proteins of Rab family [16], [17], [18], [19], [20], [21], [22], [23], eicosanoid-forming enzymes [24], [25], [26], [27], protein kinases as PI3 kinase, MAP kinase and PKC [9], [28], [29]. Therefore, lipid bodies may function not only in lipid storage and metabolism, but also in membrane trafficking and cell signaling.
Different from neutral lipid storing cells, leukocytes have virtually no lipid bodies under resting conditions. However, increased numbers of cytoplasmic lipid bodies are often associated with infectious and other inflammatory conditions [7], [27], [30], [31], [32], [33].
The organization of lipids within distinct cytoplasmic sites is a common feature of many cell types, involved in innate immune response to infections including macrophages, neutrophils, eosinophils, fibroblasts, endothelial cells, platelets, and mast cells [1], [2], [34]. However, the roles of lipid bodies in inflammatory and infectious process are frequently underestimated if lipid body defining lipid content is lost during cell staining. Indeed, drying or fixation and staining with alcohol-based reagents routinely used in hematological and histo-pathological techniques may destroy or dissolve lipid bodies. Using appropriated fixation for lipids [35] and staining with oil red O (Fig. 1A), osmium [7], [27] (Fig. 1B), or fluorescent hydrophobic probes as Nile red (Fig. 1C), bodipy (Fig. 1D) or P96 (Fig. 1E) [9], [36], [37], lipid bodies are readily identified in the cytoplasm. In addition, ADRP has been widely used as a specific marker for lipid body studies, and present a characteristic-staining pattern surrounding the lipid bodies (Fig. 1F). At the ultrastructural level, lipid bodies appear as variably osmiophilic organelles, with an electron dense shell that do not display the trilaminar structure of true membranes [38]. In addition, a new method for lipid body detection was reported by a wet scanning electron microscopy, which enables the imaging of hydrated samples and combines the rapidity of preparation of light microscopy with the resolution of electron microscopy [39].
In leukocytes, lipid bodies increase in number and size when the cells are involved in inflammatory and infectious responses. Lipid body biogenesis involves ER transfer of lipids and proteins; however the precise process involved is still a matter of debate. Three main models have been proposed: (i) formation of a neutral lipid mass synthesized by ER enzymes that is deposited in a hydrophobic domain between the two leaflets of the ER membrane; followed by budding off of this lipid structure into the cytoplasm that ends up surrounded by a half-unit membrane of phospholipids directly derived from the cytoplasmic leaflet of the ER [40], [41]; (ii) formation of lipid bodies at ADRP-enriched clusters in the cytoplasmic leaflet of ER with the transference of lipids from ER to nascent lipid bodies within ER cups, rather than between ER leaflets [42]; (iii) formation of lipid bodies by incorporation of multiple loops of ER membranous domains, with accumulation of neutral lipids among the membranes within lipid bodies [18]. Regulated lipid body biogenesis has been characterized as a cell and stimuli dependent event [2]. However, the triggering process and detailed molecular mechanisms involved in lipid body biogenesis are still a matter of intense studies. The regulated formation of lipid bodies, their proteic and lipid content and association of lipid bodies with other intracellular organelles, have established leukocyte lipid bodies as specialized, inducible intracellular domains that function as multifunctional organelles with roles in cell signaling and activation, regulation of lipid metabolism and trafficking and control the synthesis and secretion of inflammatory mediators.
Section snippets
Lipid bodies and bacterial infections
Increased lipid body accumulation in leukocytes has been observed in both clinical and experimental infectious conditions, including in cells from blood and peritoneum in bacterial sepsis [27], [43], [44], [45], bronchoalveolar lavage (BAL) of patients and experimental animals with acute respiratory distress [46], [47]; in septic arthritis [31] and foamy differentiated macrophages from granuloma or pleural lavage from mycobacterial infections [48], [49], [50], [51]. Accumulating evidence
Concluding remarks
The emerging role of lipid bodies as inflammatory organelles raises lipid body status to critical regulators of different inflammatory and infectious diseases and key markers of leukocyte activation. Notably, leukocyte lipid body biogenesis is highly regulated and is cell and stimuli specific. Lipid body structural features, including lipid and protein composition vary according to the cell type, activation state and inflammatory environment and thus may determine different cellular functions
Acknowledgements
The work of the authors is supported by PRONEX-MCT, Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq, Brazil), PAPES-FIOCRUZ, Fundação de Amparo à Pesquisa do Rio de Janeiro (FAPERJ, Brazil). The authors are indebted to Dr Christianne Bandeira-Melo for critical reading of the manuscript. We would like to thank present and past members of the Laboratory of Immunopharmacology for important contributions.
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