Polyunsaturated fatty acid metabolites: biosynthesis in Leishmania and role in parasite/host interaction

Abstract

It is the second-most lethal parasitic infection worldwide, with more than 20,000 annual deaths (http://www.who.int/leishmaniasis/en). This disease is supported by the intracellular development of a protozoan parasite belonging to the Leishmania genus. Metacyclic promastigotes are transmitted by the Phlebotominae sandfly during a blood meal on mammals, where they infect macrophages prior to differentiating into amastigote forms and proliferating inside the host cell. Procyclic promastigotes differentiate into metacyclic promastigotes during metacyclogenesis, a process that is triggered by an environmental pH decrease from neutral to acidic pH inside the sandfly vector (1, 2). Metacyclogenesis involves important morphological and biochemical modifications, and approximately 300 genes have been described to be specifically regulated according to the parasite stage (3-6). Macrophages are the primary replication site for Leishmania and the main effector cells to fight it (7). Leishmania infection leads to the development of macrophages that overexpress anti-inflammatory molecules such as interleukin (IL) 10 and transforming growth factor  and the induction of proinflammatory cytokine production such as TNF-, IL-1, and IL-6 (8). M2 macrophages control disease severity and protect the host Abstract Inside the human host, Leishmania infection starts with phagocytosis of infective promastigotes by macrophages. In order to survive, Leishmania has developed several strategies to manipulate macrophage functions. Among these strategies, Leishmania as a source of bioactive lipids has been poorly explored. Herein, we assessed the biosynthesis of polyunsaturated fatty acid metabolites by infective and noninfective stages of Leishmania and further explored the role of these metabolites in macrophage polarization. The concentration of docosahexaenoic acid metabolites, precursors of proresolving lipid mediators, was increased in the infective stage of the parasite compared with the noninfective stage, and cytochrome P450-like proteins were shown to be implicated in the biosynthesis of these metabolites. The treatment of macrophages with lipids extracted from the infective forms of the parasite led to M2 macrophage polarization and blocked the differentiation into the M1 phenotype induced by IFN-. In conclusion, Leishmania polyunsaturated fatty acid metabolites, produced by cytochrome P450-like protein activity, are implicated in parasite/host interactions by promoting the polarization of macrophages into a proresolving M2 phenotype.-Paloque, L.

Oleic acid ameliorates palmitic acid induced hepatocellular lipotoxicity by inhibition of ER stress and pyroptosis

“…As we all know, for an integral pyroptosis, the release of mature IL-1 beta is processed by three major steps: the expression of pro-IL-1 beta by activating TLR2/4 pathway, then the precursors are cut by cleaved-caspase-1, and finally matured IL-1 beta was released through GSDMD mediated-pore. These results suggested that simple ER stress, provoked by ER stressors only, was able to induce NLRP3 inflammasome, but unable to promote pro-IL-1 beta and pro-caspase-1 accumulation in HepG2 cells, probably due to lacking the activation of TLR4 pathway [35], which may be mechanistically different with PA induced ER stress and pyroptosis. An alternative explanation might be that ER stress is able to regulate GSDMD directly, resulting in membrane perforation, but the potential mechanism is expected to be further explored.…”

Lipid hijacking: A unifying theme in vector-borne diseases

“…For example, infective parasites express higher levels of polyunsaturated fatty acid metabolites and may promote the differentiation of macrophages into a less inflammatory phenotype, known as the M2 phenotype ( Paloque et al, 2019 ). These M2 macrophages produce high levels of pro-resolving bioactive lipids to facilitate parasite survival and proliferation ( Paloque et al, 2019 ). For T. cruzi , these parasites possess membrane lipids that may be involved in the induction of severe disease.…”

Immunometabolism of Leishmania granulomas

“…83 Interestingly, Leishmania-derived PUFAs polarize murine macrophages toward an M2 phenotype when added exogenously. 84 As noted earlier, Leishmania amastigotes form a tight junction with the PVM, raising the possibility that parasite lipids may be directly transported to the host cell and modulate host cell signaling. Moreover, Leishmania have recently been shown to express an aldo-keto reductase that functions as a prostaglandin F2a synthase.…”

“…PPAR‐γ–δ are activated by anti‐inflammatory cytokines (IL‐4, IL‐13, IL‐10), TLR receptors and a range of lipids and other stimuli, including oxidized low‐density lipoprotein, PUFA (arachidonic acid, 5‐hydroxyeicosatetraenoic acid and 5‐oxo‐eicosatetraenoic acid), oxidized linoleic acid (13‐HODE) and prostaglandins (D2, prostaglandin E2, prostaglandin F2, thromboxane B2), that are variously present in Leishmania granulomatous tissues 83 . Interestingly, Leishmania ‐derived PUFAs polarize murine macrophages toward an M2 phenotype when added exogenously 84 . As noted earlier, Leishmania amastigotes form a tight junction with the PVM, raising the possibility that parasite lipids may be directly transported to the host cell and modulate host cell signaling.…”