Lipopolysaccharide-Induced Leukocyte Lipid Body Formation In Vivo: Innate Immunity Elicited Intracellular Loci Involved in Eicosanoid Metabolism

Abstract

Lipid bodies are rapidly inducible, specialized cytoplasmic domains for eicosanoid-forming enzyme localization, which we hypothesize to have specific roles in enhanced inflammatory mediator production during pathological conditions, including sepsis. However, little is known about the origins, composition, or functions of lipid bodies in vivo. We show that lipid body numbers were increased in leukocytes from septic patients in comparison with healthy subjects. Analogously, the intrathoracic administration of LPS into mice induced a dose- and time-dependent increase in lipid body numbers. Pretreatment with anti-CD14 or anti-CD11b/CD18 mAb drastically inhibited LPS-induced lipid body formation. Moreover, LPS failed to form lipid bodies in C3H/HeJ (TLR4 mutated) mice, demonstrating a requisite role for LPS receptors in lipid body formation. LPS-induced lipid body formation was also inhibited by the platelet-activating factor-receptor antagonists, suggesting a role for endogenous platelet-activating factor. The eicosanoid-forming enzymes, 5-lipoxygenase and cyclooxygenase-2, were immunolocalized within experimentally induced (LPS in mice) or naturally occurring (septic patients) lipid bodies. The proinflammatory cytokine involved in the pathogenesis of sepsis, TNF-α, was also shown to colocalize within lipid bodies. Prior stimulation of leukocytes to form lipid bodies enhanced the capacity of leukocytes to produce leukotriene B4 and PGE2. In conclusion, our studies indicate that lipid bodies formed after LPS stimulation and sepsis are sites for eicosanoid-forming enzymes and cytokine localization and may develop and function as structurally distinct, intracellular sites for paracrine eicosanoid synthesis during inflammatory conditions.

Single-cell Raman and fluorescence microscopy reveal the association of lipid bodies with phagosomes in leukocytes

“…Recent work has indicated that LBs in a variety of cell types are not merely lipid reservoirs (2,3). In phagocytes engaged in inflammation, LBs have been mainly implicated in the synthesis of eicosanoids (4,5). The AA-releasing enzyme cPLA 2 , its activating mitogenactivated protein kinases, and the eicosanoid-generating enzymes 5-lipoxygenase and cyclooxygenase all have been found on the surface of LBs in several leukocyte types.…”

“…In leukocytes engaged in inflammation, an increased number of LBs is usually found (4,5). Rapid LB induction by priming agents such as cis-unsaturated fatty acids, protein kinase C activators, or platelet-activating factor has been correlated with an enhanced capacity to generate eicosanoids (6,7), which are powerful mediators of inflammation (8).…”

Leptin and mTOR: Partners in metabolism and inflammation

“…40,82 Macrophage lipid bodies, which are formed by different stimuli and pathological conditions including obesity-induced inflammation, ox-LDL-and LPS-induced inflammation or bacterial infection, are increasingly recognized as organelles with key roles in inflammation. [83][84][85][86][87][88] Under inflammatory conditions, they compartmentalize MAP kinases, cPLA 2 , eicosanoid-forming enzymes and are involved in the enhanced eicosanoid synthesis. [84][85][86][87][88][89] In addition, human colon adenocarcinoma cell lines and colon cancer biopsies from patients have recently been shown to exhibit a drastic increase in ADRP and COX-2-enriched lipid bodies.…”

“…[83][84][85][86][87][88] Under inflammatory conditions, they compartmentalize MAP kinases, cPLA 2 , eicosanoid-forming enzymes and are involved in the enhanced eicosanoid synthesis. [84][85][86][87][88][89] In addition, human colon adenocarcinoma cell lines and colon cancer biopsies from patients have recently been shown to exhibit a drastic increase in ADRP and COX-2-enriched lipid bodies. 90 Furthermore, inhibition of lipid body formation leads to inhibited PGE 2 production and correlates with diminished cancer cell proliferation.…”

Avaliação da participação de mediadores lipídicos nas infecções experimentais induzidas por diferentes isolados de Mycobacterium tuberculosis de humanos

“…Diferente dos adipócitos, nos leucócitos a formação de CLs é específica e dependente do estímulo [76][77][78] , do tipo celular [79] e de receptores [77,[80][81][82] . Os CLs são tipicamente escassos em leucócitos não ativados, mas caracteristicamente aumentados em número e tamanho in vitro e in vivo em células inflamatórias [76,[82][83][84][85][86] .…”