Publications

Metabolism of inflammation limited by AMPK and pseudo-starvation

No abstract is provided for this article.

A critical role for citrate metabolism in LPS signalling

Macrophage activation is a key event in the inflammatory process, since these cells produce a range of pro-inflammatory molecules, including ROS (reactive oxygen species), prostaglandins, cytokines and nitric oxide. These factors promote inflammation by causing vasodilation and recruitment of neutrophils, monocytes and lymphocytes, which ultimately clear infection and repair damaged tissue. One of the most potent macrophage activators is the Gram-negative-derived bacterial cell wall component LPS (lipopolysaccharide). LPS is sensed by TLR4 (Toll-like receptor 4) and triggers highly complex signalling pathways that culminate in activation of transcription factors such as NF-κB (nuclear factor κB), which in turn increases transcription of genes encoding proteins such as COX2 (cyclo-oxygenase 2, a key enzyme in prostaglandin biosynthesis), nitric oxide synthase and cytokines such as TNF (tumour necrosis factor). Recently, a role for metabolic pathways in the regulation of LPS signalling has become a focus of research in inflammation. A notable example is LPS promoting the so-called Warburg effect - aerobic glycolysis. This allows for an up-regulation in ATP production, and also for the production of biosynthetic intermediates to meet the demands of the activated macrophages. In this issue of the Biochemical Journal, Infantino et al. add a new finding to the role of metabolism in LPS action. They demonstrate a requirement for the mitochondrial citrate carrier in the induction of ROS, nitric oxide and prostaglandins by LPS. The knockdown of the carrier with siRNA (small interfering RNA), or the use of an inhibitor BTA (benzene-1,2,3-tricarboxylate), abolishes these responses. Although no mechanism is provided, the authors speculate that acetyl-CoA is synthesized from citrate in the cytosol. The acetyl-CoA generated could be required for phospholipid biosynthesis, the phospholipids being the source of arachidonic acid for prostaglandin production. Another product of citrate metabolism, oxaloacetate, will indirectly generate nitric oxide and ROS. This finding places citrate, transported from the mitochondria, as a key player in LPS signalling, at least for ROS, nitric oxide and prostaglandin production. This somewhat unexpected role for citrate in LPS action adds to a growing literature on the role for metabolism in the regulation of signalling in inflammation.

72

The NLRP3 inflammasome regulates the maturation of the pro-inflammatory cytokines IL-1 β and IL-18, which are important mediators in inflammatory disorders such as atherosclerosis, Type 2 diabetes and Alzheimer’s disease. Given its role as an inflammatory gatekeeper, NLRP3 expression is tightly controlled. It is transcriptionally regulated by NF- κ B as well as post-translationally by S-nitrosylation and ubiquitination. We decided to test whether NLRP3 is also regulated at the post-transcriptional level. We found that the NLRP3 3’ untranslated region (UTR) contains an evolutionarily conserved target site for miRNA-223 and we confirmed miR-223 as a direct negative regulator of NLRP3 using a luciferase reporter assay. Furthermore, overexpressing the miRNA reduces NLRP3 levels and IL-1 β production following activation with NLRP3 agonists. Since miR-223 is differentially expressed during myeloid differentiation, it could alter the threshold for inflammasome activation in different cell types. We have now generated a transgenic mouse deficient in the miR-223 target site in the NLRP3 3’UTR, which will allow us for the first time to study the importance of miRNA regulation of NLRP3 in vivo and in the context of inflammatory disease models. Interestingly, the human NLRP3 3’UTR can be alternatively polyadenlyated, giving rise to a truncated form of the transcript that lacks regulatory elements. While mRNA stability was not affected, a luciferase reporter assay showed that LPS stimulation could enhance expression of both 3’UTR isoforms. Using an RNA pulldown approach we identified potential RNA binding proteins that could mediate this effect. Ultimately, understanding the post-transcriptional control of NLRP3 expression will help to explain cell type-specific expression of NLRP3 and could potentially provide new opportunities to interfere with inflammasome activation in diseases such as Type 2 diabetes.

107 PKM2 is a promising novel target in atopic dermatitis

Targeting mitochondria to beat HIV-1

No abstract is provided for this article.

Reply to ”Analysis of association of the TIRAP (MAL) S180L variant and tuberculosis in three populations”

No abstract is provided for this article.

CNTF

No abstract is provided for this article.

Evidence against a role for NLRP3-driven inflammation in the db/db mouse model of type 2 diabetes

No abstract is provided for this article.

BAFF

No abstract is provided for this article.

Interaction between type 2 cytokine and inflammasome responses in the pathogenesis of obesity-associated asthma

<b>Background:</b> Obesity is a risk factor for asthma and obese asthmatics are more likely to have severe disease. How obesity affects the pathogenesis and severity of asthma is poorly understood. Roles for increased inflammasome-mediated neutrophilic responses, type-2 immunity and eosinophilic inflammation have been described but the links remain unknown. <b>Methods:</b> We assessed correlations between BMI and inflammasome responses with type-2 immune responses in the sputum of 25 subjects with asthma. Functional roles for NLRP3 inflammasome and type-2 cytokine responses in driving key features of disease were examined in experimental high fat diet-induced obesity and asthma. <b>Results:</b> BMI and inflammasome responses positively correlate with increased IL-5 and IL-13 expression, eosinophil numbers, and C-C chemokine receptor type 3 expression in the sputum of subjects with asthma. High fat diet-induced obesity results in steroid-insensitive airway hyper-responsiveness in both the presence and absence of experimental asthma. High fat diet-induced obesity is also associated with increased NLRP3 inflammasome responses and eosinophilic inflammation in airway tissue, but not the lumen. Inhibition of NLRP3 inflammasome responses reduces steroid-insensitive airway hyper-responsiveness but has no effect on IL-5 or IL-13 responses. Depletion of IL-5 and IL-13 reduces obesity-induced NLRP3 inflammasome responses and steroid-insensitive airway hyper-responsiveness. <b>Conclusion:</b> We show a relationship between type-2 cytokine and NLRP3 inflammasome responses in obesity-associated asthma, highlighting the potential utility of type-2 cytokine-targeted biologics and inflammasome inhibitors.

Evidence against a role for NLRP3-driven inflammation in the db/db mouse model of type 2 diabetes

No abstract is provided for this article.

Cutting Edge: <i>Mycobacterium tuberculosis</i> Induces Aerobic Glycolysis in Human Alveolar Macrophages That Is Required for Control of Intracellular Bacillary Replication

Recent advances in immunometabolism link metabolic changes in stimulated macrophages to production of IL-1β, a crucial cytokine in the innate immune response to Mycobacterium tuberculosis. To investigate this pathway in the host response to M. tuberculosis, we performed metabolic and functional studies on human alveolar macrophages, human monocyte-derived macrophages, and murine bone marrow-derived macrophages following infection with the bacillus in vitro. M. tuberculosis infection induced a shift from oxidative phosphorylation to aerobic glycolysis in macrophages. Inhibition of this shift resulted in decreased levels of proinflammatory IL-1β and decreased transcription of PTGS2, increased levels of anti-inflammatory IL-10, and increased intracellular bacillary survival. Blockade or absence of IL-1R negated the impact of aerobic glycolysis on intracellular bacillary survival, demonstrating that infection-induced glycolysis limits M. tuberculosis survival in macrophages through induction of IL-1β. Drugs that manipulate host metabolism may be exploited as adjuvants for future therapeutic and vaccination strategies.

Circadian Clock Proteins and Immunity

Immune parameters change with time of day and disruption of circadian rhythms has been linked to inflammatory pathologies. A circadian-clock-controlled immune system might allow an organism to anticipate daily changes in activity and feeding and the associated risk of infection or tissue damage to the host. Responses to bacteria have been shown to vary depending on time of infection, with mice being more at risk of sepsis when challenged ahead of their activity phase. Studies highlight the extent to which the molecular clock, most notably the core clock proteins BMAL1, CLOCK, and REV-ERBα, control fundamental aspects of the immune response. Examples include the BMAL1:CLOCK heterodimer regulating toll-like receptor 9 (TLR9) expression and repressing expression of the inflammatory monocyte chemokine ligand (CCL2) as well as REV-ERBα suppressing the induction of interleukin-6. Understanding the daily rhythm of the immune system could have implications for vaccinations and how we manage infectious and inflammatory diseases.

INFLAMMATION OVERVIEW AND MARKERS OF INFLAMMATION

No abstract is provided for this article.

OC 55.2 Dimethyl Fumarate and 4-Octyl Itaconate are Anticoagulants that Suppress Tissue Factor in Macrophages Via Inhibition of Type I Interferon

demonstrate the importance of systemic NET release under metabolic challenge, and how this can contribute to cardiac deterioration at a young age due to obesity-induced alteration of the innate immune system.

The anti-inflammatory cytokine IL-10 inhibits miR-155 in response to Toll-like Receptor signalling

No abstract is provided for this article.

IRAK1 and IRAK4 Promote Phosphorylation, Ubiquitination, and Degradation of MyD88 Adaptor-like (Mal)

Signal transduction by Toll-like receptor 2 (TLR2) and TLR4 requires the adaptors MyD88 and Mal (MyD88 adaptor-like) and serine/threonine kinases, interleukin-1 receptor-associated kinases IRAK1 and IRAK4. We have found that both IRAK1 and IRAK4 can directly phosphorylate Mal. In addition, co-expression of Mal with either IRAK resulted in depletion of Mal from cell lysates. This is likely to be due to Mal phosphorylation by the IRAKs because kinase-inactive forms of either IRAK had no effect. Furthermore, lipopolysaccharide stimulation resulted in ubiquitination and degradation of Mal, which was inhibited using an IRAK1/4 inhibitor or by knocking down expression of IRAK1 and IRAK4. MyD88 is not a substrate for either IRAK and did not undergo degradation. We therefore conclude that Mal is a substrate for IRAK1 and IRAK4 with phosphorylation promoting ubiquitination and degradation of Mal. This process may serve to negatively regulate signaling by TLR2 and TLR4.