Leishmania infantum lipophosphoglycan induced-Prostaglandin E2 production in association with PPAR-γ expression via activation of Toll like receptors-1 and 2

Abstract

Lipophosphoglycan (LPG) is a key virulence factor expressed on the surfaces of Leishmania promastigotes. Although LPG is known to activate macrophages, the underlying mechanisms resulting in the production of prostaglandin E2 (PGE2) via signaling pathways remain unknown. Here, the inflammatory response arising from stimulation by Leishmania infantum LPG and/or its lipid and glycan motifs was evaluated with regard to PGE2 induction. Intact LPG, but not its glycan and lipid moieties, induced a range of proinflammatory responses, including PGE2 and nitric oxide (NO) release, increased lipid droplet formation, and iNOS and COX2 expression. LPG also induced ERK-1/2 and JNK phosphorylation in macrophages, in addition to the release of PGE2, MCP-1, IL-6, TNF-α and IL-12p70, but not IL-10. Pharmacological inhibition of ERK1/2 and PKC affected PGE2 and cytokine production. Moreover, treatment with rosiglitazone, an agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ), also modulated the release of PGE2 and other proinflammatory mediators. Finally, we determined that LPG-induced PPAR-γ signaling occurred via TLR1/2. Taken together, these results reinforce the role played by L. infantum-derived LPG in the proinflammatory response seen in Leishmania infection.

Fat, fight, and beyond: The multiple roles of lipid droplets in infections and inflammation

“…Like other pathogens, some studies reported the participation of TLR in parasite‐induced LDs, as the case of TLR‐2 in the T. cruzi infection, which is amplified by the uptake of apoptotic cells in a mechanism dependent on integrins and TGF‐β synthesis . Moreover, the activation of TLR‐1 and TLR‐2 by Leishmania infantum lipophosphoglycan induced LDs accumulation in association with PPAR‐γ expression . On the other hand, LDs biogenesis was related to dysregulate host metabolism by the subversion of host mTOR and JNK signaling in the T. gondii and N. caninum infection .…”

“…47 Moreover, the activation of TLR-1 and TLR-2 by Leishmania infantum lipophosphoglycan induced LDs accumulation in association with PPAR-expression. 188 On the other hand, LDs biogenesis was related to dysregulate host metabolism by the subversion of host mTOR and JNK signaling in the T. gondii and N. caninum infection. 61 Furthermore, T. gondii promotes the expression of some triglyceride synthesis genes and lipid transporters, and inhibits the expression of lipolytic genes, especially ATGL, favoring the LD accumulation in the host cell.…”

Leishmania donovani Lipophosphoglycan Increases Macrophage-Dependent Chemotaxis of CXCR6-Expressing Cells via CXCL16 Induction

“…LPG is one of the major surface glycoconjugates of Leishmania promastigotes and plays a central role in the establishment of infection (17). Importantly, macrophages secrete several immune mediators following exposure to purified LPG (25)(26)(27)(28). Therefore, we hypothesized that this virulence factor could be implicated in the upregulation of CXCL16 in L. donovani-infected macrophages.…”

“…Notably, LPG prevents phagosome maturation (20), inhibits phagosomal acidification and oxidative burst (21,22), reduces the phagocytic capacity of host macrophages (23), and hampers the lytic action of the complement system (24). In addition to its inhibitory effects, extensive work supports the notion that LPG alters macrophage signaling and contributes to the inflammatory response triggered during Leishmania infection (25)(26)(27)(28)(29). For example, L. mexicana LPG stimulates the synthesis of TNF, interleukin-1␤ (IL-1␤), IL-12, and nitric oxide (NO) through the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) signaling (28).…”

“…Similarly, L. amazonensis LPG and L. braziliensis LPG upregulate NO and TNF production via TLR2-and TLR4-mediated mechanisms (27). More recently, it was shown that L. infantum LPG interacts with TLR1/2, activates ERK1/2 and Jun N-terminal protein kinase (JNK) signaling, and induces the release of prostaglandin E 2 , NO, TNF, IL-6, IL-12, and CCL2 (25). Although less investigated than for other Leishmania spp., purified L. donovani LPG also modulates proinflammatory mediator production, as evidenced by the upregulation of the nuclear translocation of the transcription factor AP-1 and the synthesis of NO in a macrophage cell line (29).…”