Francisella tularensis LVS Induction of Prostaglandin Biosynthesis by Infected Macrophages Requires Specific Host Phospholipases and Lipid Phosphatases

Navratil, Aaron R.; Brummett, Ashley M.; Bryan, Joshua; Woolard, Matthew D.

doi:10.1128/iai.02060-14

Cited by 13 publications

(14 citation statements)

References 64 publications

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“…To investigate the contribution of lipin-1 to foam cell formation, we used the RAW264.7 macrophage cell line, in which we generated stable lipin-1 knockdown using a lentivirally delivered shRNA (80% knockdown). We have previously demonstrated both the successful and specific knockdown of lipin-1 in RAW264.7 macrophages 15 . Wild-type (WT), non-target (NT) or lipin-1 depleted RAW264.7 macrophages were mock treated or treated with oxLDL (10 μg/mL) or acLDL (50 μg/mL) for 24 hours.…”

Section: Resultsmentioning

confidence: 99%

“…Macrophages require lipin-1 for PGE 2 and pro-inflammatory cytokine production in response to LPS and the intracellular bacteria Francisella tularensis 15–16 . We demonstrate here that short-term oxLDL treatment (24 hours) fails to elicit pro-inflammatory cytokine responses, in agreement with work by Spann et.al, who demonstrated that cholesterol uptake by macrophages results in an anti-inflammatory macrophage phenotype 33 .…”

Section: Discussionmentioning

confidence: 99%

“…In human and mouse macrophages, lipin-1 contributes to lipid droplet formation following fatty acid loading 14 . Additionally, we and others have demonstrated that lipin-1 regulates macrophage inflammatory activity in response to both the intracellular pathogen Francisella tularensis 15 and to lipopolysaccharide (LPS) 16 . These studies demonstrate that lipin-1 is involved in two cellular events that are known to exist in macrophage foam cells; storage of engulfed cholesterol/lipids and pro-inflammatory activity, suggesting to us that lipin-1 may link lipid synthesis pathways that contribute to foam cell formation to foam cell inflammatory mediator production.…”

Section: Introductionmentioning

confidence: 97%

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Lipin-1 contributes to modified low-density lipoprotein-elicited macrophage pro-inflammatory responses

et al. 2015

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Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries and the underlying cause of cardiovascular disease, a major cause of mortality worldwide. The over-accumulation of modified cholesterol-containing low-density lipoproteins (e.g. oxLDL) in the artery wall and the subsequent recruitment and activation of macrophages contributes to the development of atherosclerosis. The excessive uptake of modified-LDL by macrophages leads to a lipid-laden “foamy” phenotype and pro-inflammatory cytokine production. Modified-LDLs promote foam cell formation in part by stimulating de novo lipid biosynthesis. However, it is unknown if lipid biosynthesis directly regulates foam cell pro-inflammatory mediator production. Lipin-1, a phosphatidate phosphohydrolase required for the generation of diacylglycerol during glycerolipid synthesis has recently been demonstrated to contribute to bacterial-induced pro-inflammatory responses by macrophages. In this study we present evidence demonstrating the presence of lipin-1 within macrophages in human atherosclerotic plaques. Additionally, reducing lipin-1 levels in macrophages significantly inhibits both modified-LDL-induced foam cell formation in vitro, as observed by smaller/fewer intracellular lipid inclusions, and ablates modified-LDL-elicited production of the pro-atherogenic mediators tumor necrosis factor-α, interleukin-6, and prostaglandin E2. These findings demonstrate a critical role for lipin-1 in the regulation of macrophage inflammatory responses to modified-LDL. These data begin to link the processes of foam cell formation and pro-inflammatory cytokine production within macrophages.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Lipin-1 contributes to modified low-density lipoprotein-elicited macrophage pro-inflammatory responses

et al. 2015

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“…The increased survival outcome resulting from the reduction of PGE2 production during bacterial infections through COX-2 inhibition and reduction in NF-ĸB activation has profound implications. PGE2 is produced during a number of lethal bacterial infections (i.e Francisella tularesis [23]) and opportunistic bacterial infections ( Pseudomonas aeruginosa and Staphylococcus aereus ) for which antibacterial treatment is complex due to antibacterial resistance [24] [25]. Proving the efficacy of immunotherapy using commercially available, orally administered TA in combination with sub-therapeutic antibiotic treatment during melioidosis in BALB/c mice warrants further investigation in other animal models of melioidosis.…”

Section: Discussionmentioning

confidence: 99%

Immune Modulation as an Effective Adjunct Post-exposure Therapeutic for B. pseudomallei

et al. 2016

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Melioidosis is caused by the facultative intracellular bacterium Burkholderia pseudomallei and is potentially fatal. Despite a growing global burden and high fatality rate, little is known about the disease. Recent studies demonstrate that cyclooxygenase-2 (COX-2) inhibition is an effective post-exposure therapeutic for pulmonary melioidosis, which works by inhibiting the production of prostaglandin E2 (PGE2). This treatment, while effective, was conducted using an experimental COX-2 inhibitor that is not approved for human or animal use. Therefore, an alternative COX-2 inhibitor needs to be identified for further studies. Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug (NSAID) COX-2 inhibitor marketed outside of the United States for the treatment of migraines. While this drug was developed for COX-2 inhibition, it has been found to modulate other aspects of inflammation as well. In this study, we used RAW 264.7 cells infected with B pseudomallei to analyze the effect of TA on cell survival, PGE2 production and regulation of COX-2 and nuclear factor- kappaB (NF-ĸB) protein expression. To evaluate the effectiveness of post-exposure treatment with TA, results were compared to Ceftazidime (CZ) treatments alone and the co-treatment of TA with a sub-therapeutic treatment of CZ determined in a study of BALB/c mice. Results revealed an increase in cell viability in vitro with TA and were able to reduce both COX-2 expression and PGE2 production while also decreasing NF-ĸB activation during infection. Co-treatment of orally administered TA and a sub-therapeutic treatment of CZ significantly increased survival outcome and cleared the bacterial load within organ tissue. Additionally, we demonstrated that post-exposure TA treatment with sub-therapeutic CZ is effective to treat melioidosis in BALB/c mice.

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“…44 Once differentiated, BMDM were washed with PBS, seeded for the appropriate downstream assay, allowed to adhere for 2 hours in complete DMEM, and subsequently incubated with conditioned media (CM) from control and colitic acute 2% DSS-induced C57BL/6J mice, as previously described. 17 In the IF groups, CM was supplemented with cytochalasin D (10 μm; Sigma).…”

Section: Methodsmentioning

confidence: 99%

A Critical Role for Monocytes/Macrophages During Intestinal Inflammation-associated Lymphangiogenesis

Becker

Kurmaeva

Gavins

et al. 2016

Inflammatory Bowel Diseases

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Background Inflammation-associated lymphangiogenesis (IAL) is frequently observed in inflammatory bowel diseases. IAL is believed to limit inflammation by enhancing fluid and immune cell clearance. Although monocytes/macrophages (MΦ) are known to contribute to intestinal pathology in inflammatory bowel disease, their role in intestinal IAL has never been studied mechanistically. We investigated contributions of monocytes/MΦ to the development of intestinal inflammation and IAL. Methods Because inflammatory monocytes express CC chemokine receptor 2 (CCR2), we used CCR2 diphtheria toxin receptor transgenic (CCR2.DTR) mice, in which monocytes can be depleted by diphtheria toxin injection, and CCR2−/− mice, which have reduced circulating monocytes. Acute or chronic colitis was induced by dextran sodium sulfate or adoptive transfer of CD4+CD45RBhigh T cells, respectively. Intestinal inflammation was assessed by flow cytometry, immunofluorescence, disease activity, and histopathology, whereas IAL was assessed by lymphatic vessel morphology and density. Results We demonstrated that intestinal MΦ expressed vascular endothelial growth factor-C/D. In acute colitis, monocyte-depleted mice were protected from intestinal injury and showed reduced IAL, which was reversed after transfer of wild-type monocytes into CCR2−/− mice. In chronic colitis, CCR2 deficiency did not attenuate inflammation but reduced IAL. Conclusions We propose a dual role of MΦ in (1) promoting acute inflammation and (2) contributing to IAL. Our data suggest that intestinal inflammation and IAL could occur independently, because IAL was reduced in the absence of monocytes/MΦ, even when inflammation was present. Future inflammatory bowel disease therapies might exploit promotion of IAL and suppression of MΦ independently, to restore lymphatic clearance and reduce inflammation.

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Francisella tularensis LVS Induction of Prostaglandin Biosynthesis by Infected Macrophages Requires Specific Host Phospholipases and Lipid Phosphatases

Cited by 13 publications

References 64 publications

Lipin-1 contributes to modified low-density lipoprotein-elicited macrophage pro-inflammatory responses

Lipin-1 contributes to modified low-density lipoprotein-elicited macrophage pro-inflammatory responses

Immune Modulation as an Effective Adjunct Post-exposure Therapeutic for B. pseudomallei

A Critical Role for Monocytes/Macrophages During Intestinal Inflammation-associated Lymphangiogenesis

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