Lipid bodies in innate immune response to bacterial and parasite infections

https://doi.org/10.1016/j.intimp.2008.01.035Get rights and content

Abstract

Lipid bodies (also known as lipid droplets, adiposomes) are dynamic organelles with key roles in regulating storage and turnover of lipids in different cells and organisms. 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 cell activation. Notably, lipid body biogenesis is highly regulated and is cell and stimuli specific. Lipid body structural features, including lipid and protein composition may vary according to the cell type, activation state and inflammatory environment and thus may determine different cellular functions for lipid bodies. Here we will review the morphological and structural aspects of lipid bodies, the regulated mechanisms of formation, as well as lipid body functions in cells involved in the innate immune response during 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.

References (88)

  • D.L. Brasaemle et al.

    Proteomic analysis of proteins associated with lipid droplets of basal and lipolytically stimulated 3T3-L1 adipocytes

    J Biol Chem

    (2004)
  • S. Martin et al.

    Regulated localization of Rab18 to lipid droplets: effects of lipolytic stimulation and inhibition of lipid droplet catabolism

    J Biol Chem

    (2005)
  • W. Yu et al.

    Phosphatidylinositide 3-kinase localizes to cytoplasmic lipid bodies in human polymorphonuclear leukocytes and other myeloid-derived cells

    Blood

    (2000)
  • R.C. Melo et al.

    Macrophage lipid body induction by Chagas disease in vivo: putative intracellular domains for eicosanoid formation during infection

    Tissue Cell

    (2003)
  • R.C. Melo et al.

    Leukocyte lipid bodies: inflammation-related organelles are rapidly detected by wet scanning electron microscopy

    J Lipid Res

    (2006)
  • D.A. Brown

    Lipid droplets: proteins floating on a pool of fat

    Curr Biol

    (2001)
  • J.I. Salluh et al.

    Lung production of platelet-activating factor acetylhydrolase in oleic acid-induced acute lung injury

    Prostaglandins Leukot Essent Fat Acids

    (2007)
  • D.S. Ridley et al.

    Rationale for the histological spectrum of tuberculosis. A basis for classification

    Pathology

    (1987)
  • S. Akira

    Toll-like receptor signaling

    J Biol Chem

    (2003)
  • C. Bandeira-Melo et al.

    Extranuclear lipid bodies, elicited by CCR3-mediated signaling pathways, are the sites of chemokine-enhanced leukotriene C4 production in eosinophils and basophils

    J Biol Chem

    (2001)
  • Y. Kumar et al.

    The obligate intracellular pathogen Chlamydia trachomatis targets host lipid droplets

    Curr Biol

    (2006)
  • P. Liu et al.

    Rab-regulated interaction of early endosomes with lipid droplets

    Biochim Biophys Acta

    (2007)
  • A.M. Celentano et al.

    PGE2 involvement in experimental infection with Trypanosoma cruzi subpopulations

    Prostaglandins

    (1995)
  • M.M. Borges et al.

    Prostaglandin and nitric oxide regulate TNF-alpha production during Trypanosoma cruzi infection

    Immunol Lett

    (1998)
  • T.P. Combs et al.

    The adipocyte as an important target cell for Trypanosoma cruzi infection

    J Biol Chem

    (2005)
  • I. Coppens et al.

    Insights into unique physiological features of neutral lipids in Apicomplexa: from storage to potential mediation in parasite metabolic activities

    Int J Parasitol

    (2005)
  • O. Vielemeyer et al.

    Neutral lipid synthesis and storage in the intraerythrocytic stages of Plasmodium falciparum

    Mol Biochem Parasitol

    (2004)
  • J.B. Correa Soares et al.

    Extracellular lipid droplets promote hemozoin crystallization in the gut of the blood fluke Schistosoma mansoni

    FEBS Lett

    (2007)
  • M. Waltermann et al.

    Mechanism of lipid-body formation in prokaryotes: how bacteria fatten up

    Mol Microbiol

    (2005)
  • P.F. Weller et al.

    Cytoplasmic lipid bodies of human neutrophilic leukocytes

    Am J Pathol

    (1989)
  • P.F. Weller et al.

    Cytoplasmic lipid bodies of neutrophils: formation induced by cis-unsaturated fatty acids and mediated by protein kinase C

    J Cell Biol

    (1991)
  • M.M. Johnson et al.

    Role of arachidonyl triglycerides within lipid bodies in eicosanoid formation by human polymorphonuclear cells

    Am J Respir Cell Mol Biol

    (1999)
  • W. Yu et al.

    Co-compartmentalization of MAP kinases and cytosolic phospholipase A2 at cytoplasmic arachidonate-rich lipid bodies

    Am J Pathol

    (1998)
  • H.W. Heid et al.

    Adipophilin is a specific marker of lipid accumulation in diverse cell types and diseases

    Cell Tissue Res

    (1998)
  • H.C. Wan et al.

    Roles and origins of leukocyte lipid bodies: proteomic and ultrastructural studies

    FASEB J

    (2007)
  • S. Ozeki et al.

    Rab18 localizes to lipid droplets and induces their close apposition to the endoplasmic reticulum-derived membrane

    J Cell Sci

    (2005)
  • T. Fujimoto et al.

    Caveolin-2 is targeted to lipid droplets, a new “membrane domain” in the cell

    J Cell Biol

    (2001)
  • A. Pol et al.

    A caveolin dominant negative mutant associates with lipid bodies and induces intracellular cholesterol imbalance

    J Cell Biol

    (2001)
  • A. Pol et al.

    Dynamic and regulated association of caveolin with lipid bodies: modulation of lipid body motility and function by a dominant negative mutant

    Mol Biol Cell

    (2004)
  • A.M. Dvorak et al.

    Ultrastructural localization of prostaglandin endoperoxide synthase (cyclooxygenase) to isolated, purified fractions of guinea pig peritoneal macrophage and line 10 hepatocarcinoma cell lipid bodies

    Int Arch Allergy Immunol

    (1993)
  • P.T. Bozza et al.

    Eosinophil lipid bodies: specific, inducible intracellular sites for enhanced eicosanoid formation

    J Exp Med

    (1997)
  • P.T. Bozza et al.

    Pathways for eosinophil lipid body induction: differing signal transduction in cells from normal and hypereosinophilic subjects

    J Leukoc Biol

    (1998)
  • P. Pacheco et al.

    Lipopolysaccharide-induced leukocyte lipid body formation in vivo: innate immunity elicited intracellular loci involved in eicosanoid metabolism

    J Immunol

    (2002)
  • J.S. Chen et al.

    Oleic acid-induced PKC isozyme translocation in RAW 264.7 macrophages

    J Cell Biochem

    (2002)
  • Cited by (56)

    • Involvement of lipids from Leishmania braziliensis promastigotes and amastigotes in macrophage activation

      2020, Molecular Immunology
      Citation Excerpt :

      These organelles, present in the cytoplasm of most eukaryotic cells, are critical regulators of different inflammatory diseases and crucial markers of leukocyte activation. LB compartmentalize eicosanoid forming enzymes such as cyclooxygenase-2 (COX-2), which regulate the production of diverse inflammatory mediators (Bozza et al., 2009; D’Avila et al., 2008). In this concern, expression of LB has been reported during infection with L. major and L. amazoniensis promastigotes (Pinheiro et al., 2009; Rabhi et al., 2016).

    • Leptin regulation of immune responses

      2016, Trends in Molecular Medicine
    • Differential TLR2 downstream signaling regulates lipid metabolism and cytokine production triggered by Mycobacterium bovis BCG infection

      2014, Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
      Citation Excerpt :

      As observed for other pathological conditions, the foam aspect of macrophages during mycobacteria infection is a reflection of intracellular lipid accumulation. Accumulated evidence demonstrated that newly formed lipid bodies are structurally distinct cytoplasmic organelles involved in lipid mediator synthesis with immunomodulatory functions during Mycobacterium bovis BCG infection [5,14,15]. In addition, mycobacteria induction and targeting to lipid body may provide an escape mechanism during infection due to down-modulation of the macrophage response and/or acquisition of nutrients, leading to enhanced survival and replication in host cells [5,13,16,17].

    • Innate immunity stimulates permeability barrier homeostasis

      2013, Journal of Investigative Dermatology
    • Involvement of lipid droplets in hepatic responses to lipopolysaccharide treatment in mice

      2013, Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
      Citation Excerpt :

      These proteins have been implicated in the assembly, the biogenesis and the regulation of lipolysis of LDs [1,2]. LDs also seem to play a role in the compartmentalization of proteins related to lipid metabolism, caveolins, proteins of the Rab family and components of intracellular signaling pathways (e.g. many kinases; reviewed in [3]). Therefore, LDs may function not only in lipid storage and metabolism but also in cell signaling, organelle communication and membrane trafficking.

    View all citing articles on Scopus
    View full text