Cholesterol metabolism: a new molecular switch to control inflammation.

The immune system protects the body against harm by inducing inflammation. During the immune response, cells of the immune system get activated, divided and differentiated in order to eliminate the danger signal. This process relies on the metabolic reprogramming of both catabolic and anabolic pathways not only to produce energy in the form of ATP but also to generate metabolites that exert key functions in controlling the response. Equally important to mounting an appropriate effector response is the process of immune resolution, as uncontrolled inflammation is implicated in the pathogenesis of many human diseases, including allergy, chronic inflammation and cancer. In this review, we aim to introduce the reader to the field of cholesterol immunometabolism and discuss how both metabolites arising from the pathway and cholesterol homeostasis are able to impact innate and adaptive immune cells, staging cholesterol homeostasis at the centre of an adequate immune response. We also review evidence that demonstrates the clear impact that cholesterol metabolism has in both the induction and the resolution of the inflammatory response. Finally, we propose that emerging data in this field not only increase our understanding of immunometabolism but also provide new tools for monitoring and intervening in human diseases, where controlling and/or modifying inflammation is desirable.

Cholesterol loading suppresses the atheroinflammatory gene polarization of human macrophages induced by colony stimulating factors.

In atherosclerotic lesions, blood-derived monocytes differentiate into distinct macrophage subpopulations, and further into cholesterol-filled foam cells under a complex milieu of cytokines, which also contains macrophage-colony stimulating factor (M-CSF) and granulocyte-macrophage-colony stimulating factor (GM-CSF). Here we generated human macrophages in the presence of either M-CSF or GM-CSF to obtain M-MØ and GM-MØ, respectively. The macrophages were converted into cholesterol-loaded foam cells by incubating them with acetyl-LDL, and their atheroinflammatory gene expression profiles were then assessed. Compared with GM-MØ, the M-MØ expressed higher levels of CD36, SRA1, and ACAT1, and also exhibited a greater ability to take up acetyl-LDL, esterify cholesterol, and become converted to foam cells. M-MØ foam cells expressed higher levels of ABCA1 and ABCG1, and, correspondingly, exhibited higher rates of cholesterol efflux to apoA-I and HDL2. Cholesterol loading of M-MØ strongly suppressed the high baseline expression of CCL2, whereas in GM-MØ the low baseline expression CCL2 remained unchanged during cholesterol loading. The expression of TNFA, IL1B, and CXCL8 were reduced in LPS-activated macrophage foam cells of either subtype. In summary, cholesterol loading converged the CSF-dependent expression of key genes related to intracellular cholesterol balance and inflammation. These findings suggest that transformation of CSF-polarized macrophages into foam cells may reduce their atheroinflammatory potential in atherogenesis.

Liver X Receptors: Regulators of Cholesterol Metabolism, Inflammation, Autoimmunity, and Cancer.

The interplay between cellular stress and immune response can be variable and sometimes contradictory. The mechanisms by which stress-activated pathways regulate the inflammatory response to a pathogen, in autoimmunity or during cancer progression remain unclear in many aspects, despite our recent knowledge of the signalling and transcriptional pathways involved in these diseases. In this context, over the last decade many studies demonstrated that cholesterol metabolism is an important checkpoint for immune homeostasis and cancer progression. Indeed, cholesterol is actively metabolized and can regulate, through its mobilization and/or production of active derivatives, many aspects of immunity and inflammation. Moreover, accumulation of cholesterol has been described in cancer cells, indicating metabolic addiction. The nuclear receptors liver-X-receptors (LXRs) are important regulators of intracellular cholesterol and lipids homeostasis. They have also key regulatory roles in immune response, as they can regulate inflammation, innate and adaptive immunity. Moreover, activation of LXRs has been reported to affect the proliferation and survival of different cancer cell types that show altered metabolic pathways and accumulation of cholesterol. In this minireview we will give an overview of the recent understandings about the mechanisms through which LXRs regulate inflammation, autoimmunity, and cancer, and the therapeutic potential for future treatment of these diseases through modulation of cholesterol metabolism.

Protein arginine methyltransferase 5 promotes cholesterol biosynthesis-mediated Th17 responses and autoimmunity.

Protein arginine methyltransferase 5 (PRMT5) catalyzes symmetric dimethylation (SDM) of arginine, a posttranslational modification involved in oncogenesis and embryonic development. However, the role and mechanisms by which PRMT5 modulates Th cell polarization and autoimmune disease have not yet been elucidated. Here, we found that PRMT5 promoted SREBP1 SDM and the induction of cholesterol biosynthetic pathway enzymes that produce retinoid-related orphan receptor (ROR) agonists that activate RORγt. Specific loss of PRMT5 in the CD4+ Th cell compartment suppressed Th17 differentiation and protected mice from developing experimental autoimmune encephalomyelitis (EAE). We also found that PRMT5 controlled thymic and peripheral homeostasis in the CD4+ Th cell life cycle and invariant NK (iNK) T cell development and CD8+ T cell maintenance. This work demonstrates that PRMT5 expression in recently activated T cells is necessary for the cholesterol biosynthesis metabolic gene expression program that generates RORγt agonistic activity and promotes Th17 differentiation and EAE. These results point to Th PRMT5 and its downstream cholesterol biosynthesis pathway as promising therapeutic targets in Th17-mediated diseases.

Dietary Toll-Like Receptor Stimulants Promote Hepatic Inflammation and Impair Reverse Cholesterol Transport in Mice via Macrophage-Dependent Interleukin-1 Production.

Background: The mechanisms connecting dietary intake of processed foods with systemic inflammatory markers and cardiovascular risk remain poorly defined. We sought to compare the abundance of pro-inflammatory stimulants of innate immune receptors in processed foods with those produced by the murine ileal and caecal microbiota, and to explore the impact of their ingestion on systemic inflammation and lipid metabolism in vivo. Methods and results: Calibrated receptor-dependent reporter assays revealed that many processed foods, particularly those based on minced meats, contain pro-inflammatory stimulants of Toll-like receptor (TLR)-2 and TLR4 at concentrations which greatly exceed those produced by the endogenous murine ileal microbiota. Chronic dietary supplementation with these stimulants, at concentrations relevant to those measured in the Western diet, promoted hepatic inflammation and reduced several markers of reverse cholesterol transport (RCT) in mice. Hepatocytes were found to be insensitive to TLR2- and TLR4-stimulants directly, but their secretion of functional cholesterol acceptors was impaired by interleukin (IL)-1ß released by TLR-responsive hepatic macrophages. Hepatic macrophage priming by high-fat diet enhanced the impairment of RCT by ingested endotoxin, and this was reversed by macrophage depletion via clodronate liposome treatment, or genetic deficiency in the IL-1 receptor. Conclusion: These findings reveal an unexpected mechanism connecting processed food consumption with cardiovascular risk factors, and introduce the food microbiota as a potential target for therapeutic regulation of lipid metabolism.

Immunometabolic function of cholesterol in cardiovascular disease and beyond.

Inflammation represents the driving feature of many diseases, including atherosclerosis, cancer, autoimmunity and infections. It is now established that metabolic processes shape a proper immune response and within this context the alteration in cellular cholesterol homeostasis has emerged as a culprit of many metabolic abnormalities observed in chronic inflammatory diseases. Cholesterol accumulation supports the inflammatory response of myeloid cells (i.e. augmentation of toll-like receptor signalling, inflammasome activation, and production of monocytes and neutrophils) which is beneficial in the response to infections, but worsens diseases associated with chronic metabolic inflammation including atherosclerosis. In addition to the innate immune system, cells of adaptive immunity, upon activation, have also been shown to undergo a reprogramming of cellular cholesterol metabolism, which results in the amplification of inflammatory responses. Aim of this review is to discuss (i) the molecular mechanisms linking cellular cholesterol metabolism to specific immune functions; (ii) how cellular cholesterol accumulation sustains chronic inflammatory diseases such as atherosclerosis; (iii) the immunometabolic profile of patients with defects of genes affecting cholesterol metabolism including familial hypercholesterolaemia, cholesteryl ester storage disease, Niemann-Pick type C, and immunoglobulin D syndrome/mevalonate kinase deficiency. Available data indicate that cholesterol immunometabolism plays a key role in directing immune cells function and set the stage for investigating the repurposing of existing 'metabolic' drugs to modulate the immune response.

Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers.

Understanding the tumor immune microenvironment (TIME) promises to be key for optimal cancer therapy, especially in triple-negative breast cancer (TNBC). Integrating spatial resolution of immune cells with laser capture microdissection gene expression profiles, we defined distinct TIME stratification in TNBC, with implications for current therapies including immune checkpoint blockade. TNBCs with an immunoreactive microenvironment exhibited tumoral infiltration of granzyme B+CD8+ T cells (GzmB+CD8+ T cells), a type 1 IFN signature, and elevated expression of multiple immune inhibitory molecules including indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand 1 (PD-L1), and resulted in good outcomes. An "immune-cold" microenvironment with an absence of tumoral CD8+ T cells was defined by elevated expression of the immunosuppressive marker B7-H4, signatures of fibrotic stroma, and poor outcomes. A distinct poor-outcome immunomodulatory microenvironment, hitherto poorly characterized, exhibited stromal restriction of CD8+ T cells, stromal expression of PD-L1, and enrichment for signatures of cholesterol biosynthesis. Metasignatures defining these TIME subtypes allowed us to stratify TNBCs, predict outcomes, and identify potential therapeutic targets for TNBC.

Differential response of T cells to an immunogen, a mitogen and a chemical carcinogen in a mouse model system.

In this study, we examined the relative immune response of T-lymphocytes and its intracellular cholesterol homeostasis, in a mouse model system, after treatment with immunogen, mitogen, and carcinogen. We studied the T-lymphocyte percentage, their LDL-receptor expression, along with the levels of serum interleukins (IL-2, IFNγ, IL-4, and IL-10) and intracellular cholesterol concentration (cytoplasmic and nuclear). The mitogen was found to be a better stimulator of T-cell marker expressions than the immunogen; though the immunogen was more effective on immunogenic response as was marked from interleukin levels. The chemical carcinogen benzo-α-pyrene at low concentration acted potentially like a mitogen but a reduced immune response was apparent at a carcinogenic dose. The findings in our study focus on the effect of carcinogenic dose of benzo-α-pyrene (BaP) on T-cell immunity. Benzo-α-pyrene causes immunosuppression through restriction of the T-cell population by targeting intracellular cholesterol.

The novel immunogenic chimeric peptide vaccine to elicit potent cellular and mucosal immune responses against HTLV-1.

This study reports on the immunogenicity assessment of a novel chimeric peptide vaccine including Tax, gp21, gp46, and gag immunodominant epitopes of human T-cell lymphotropic virus type 1 (HTLV-1) to induce immunity against HTLV-1 after subcutaneous (SC) or intranasal administration in a mice model. Additionally, to elevate the efficacy of the HTLV-1 vaccine, the chimera was physically mixed with monophosphoryl lipid A (MPLA) or ISCOMATRIX (IMX) adjuvants. For this purpose, the ISCOMATRIX with a size range of 40-60 nm were prepared using lipid film hydration method. Our investigation revealed that the mixture of IMX and chimera could significantly increase antibody titers containing IgG2a, and mucosal IgA, as well as IFN-γ and IL-10 cytokines and decrease the level of TGF-ß1, compared to other vaccine formulations. The intranasal delivery of chimera vaccine in the absence or presence adjuvants stimulated potent mucosal sIgA titer relative to subcutaneous immunization. Furthermore, the SC or nasal delivery of various vaccine formulations could shift the immunity toward cell-mediated responses, as evident by higher IgG2a and IFN-γ, as well as suppressed TGF-ß1 level. Our findings suggest that proper design, construction, and immunization of multi-epitope vaccine are essential for developing an effective HTLV-1 vaccine.

The role of lipids in host-pathogen interactions.

Innate immunity relies on the effective recognition and elimination of pathogenic microorganisms. This entails sequestration of pathogens into phagosomes that promptly acquire microbicidal and degradative properties. This complex series of events, which involve cytoskeletal reorganization, membrane remodeling and the activation of multiple enzymes, is orchestrated by lipid signaling. To overcome this immune response, intracellular pathogens acquired mechanisms to subvert phosphoinositide-mediated signaling and use host lipids, notably cholesterol, as nutrients. We present brief overviews of the role of phosphoinositides in phagosome formation and maturation as well as of cholesterol handling by host cells, and selected Salmonella, Shigella, Chlamydia and Mycobacterium tuberculosis to exemplify the mechanisms whereby intracellular pathogens co-opt lipid metabolism in host cells. © 2018 IUBMB Life, 70(5):384-392, 2018.

Macrophages and lipid metabolism.

Distinct macrophage populations throughout the body display highly heterogeneous transcriptional and epigenetic programs. Recent research has highlighted that these profiles enable the different macrophage populations to perform distinct functions as required in their tissue of residence, in addition to the prototypical macrophage functions such as in innate immunity. These 'extra' tissue-specific functions have been termed accessory functions. One such putative accessory function is lipid metabolism, with macrophages in the lung and liver in particular being associated with this function. As it is now appreciated that cell metabolism not only provides energy but also greatly influences the phenotype and function of the cell, here we review how lipid metabolism affects macrophage phenotype and function and the specific roles played by macrophages in the pathogenesis of lipid-related diseases. In addition, we highlight the current questions limiting our understanding of the role of macrophages in lipid metabolism.

The role of monocytosis and neutrophilia in atherosclerosis.

Monocytosis and neutrophilia are frequent events in atherosclerosis. These phenomena arise from the increased proliferation of hematopoietic stem and multipotential progenitor cells (HSPCs) and HSPC mobilization from the bone marrow to other immune organs and circulation. High cholesterol and inflammatory signals promote HSPC proliferation and preferential differentiation to the myeloid precursors (i.e., myelopoiesis) that than give rise to pro-inflammatory immune cells. These cells accumulate in the plaques thereby enhancing vascular inflammation and contributing to further lesion progression. Studies in animal models of atherosclerosis showed that manipulation with HSPC proliferation and differentiation through the activation of LXR-dependent mechanisms and restoration of cholesterol efflux may have a significant therapeutic potential.

Immunometabolic Effect of Cholesterol in Hepatitis C Infection: Implications in Clinical Management and Antiviral Therapy.

Hepatitis C virus (HCV) is a lipid-enveloped virion particle that causes infection to the liver, and as part of its life cycle, it disrupts the host lipid metabolic machinery, particularly the cholesterol synthesis pathway. The innate immune response generated by liver resident immune cells is responsible for successful viral eradication. Unfortunately, most patients fail to eliminate HCV and progress to chronic infection. Chronic infection is associated with hepatic fat accumulation and inflammation that triggers fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Despite that the current direct-acting antiviral agents have increased the cure rate of HCV infection, viral genotype and the host genetic background influence both the immune response and lipid metabolism. In this context, recent evidence has shown that cholesterol and its derivatives such as oxysterols might modulate and potentialize the hepatic innate immune response generated against HCV. The impairment of the HCV life cycle modulated by serum cholesterol could be relevant for the clinical management of HCV-infected patients before and after treatment. Alongside, cholesterol levels are modulated either by genetic variations in IL28B, ApoE, and LDLR or by dietary components. Indeed, some nutrients such as unsaturated fatty acids have demonstrated to be effective against HCV replication. Thus, cholesterol modifications may be considered as a new adjuvant strategy for HCV infection therapy by providing a biochemical tool that guides treatment decisions, an improved treatment response and favoring viral clearance. Herein, the mechanisms by which cholesterol contributes to the immune response against HCV infection and how genetic and environmental factors may affect this role are reviewed.

Inhibition of the NLRP3 inflammasome attenuates foam cell formation of THP-1 macrophages by suppressing ox-LDL uptake and promoting cholesterol efflux.

The NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome plays an important role in the development of atherosclerosis. The activated NLRP3 inflammasome has been reported to promote macrophage foam cell formation, but not all studies have obtained the same result, and how NLRP3 inflammasome is involved in the formation of foam cells remains elusive. We used selective NLRP3 inflammasome inhibitors and NLRP3-deficient THP-1 cells to assess the effect of NLRP3 inflammasome inhibition on macrophage foam cell formation, oxidized low-density lipoprotein (ox-LDL) uptake, esterification, and cholesterol efflux, as well as the expression of associated proteins. Inhibition of the NLRP3 inflammasome attenuated foam cell formation, diminished ox-LDL uptake, and promoted cholesterol efflux from THP-1 macrophages. Moreover, it downregulated CD36, acyl coenzyme A: cholesterol acyltransferase-1 and neutral cholesterol ester hydrolase expression; upregulated ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-BI) expression; but had no effect on the expression of scavenger receptor class A and ATP-binding cassette transporter G1. Collectively, our findings show that inhibition of the NLRP3 inflammasome decreases foam cell formation of THP-1 macrophages via suppression of ox-LDL uptake and enhancement of cholesterol efflux, which may be due to downregulation of CD36 expression and upregulation of ABCA1 and SR-BI expression, respectively.

The transcription factor MafB promotes anti-inflammatory M2 polarization and cholesterol efflux in macrophages.

Macrophages play pivotal roles in the progression and regression of atherosclerosis. Accumulating evidence suggests that macrophage polarization into an anti-inflammatory M2 state is a key characteristic of atherosclerotic plaques undergoing regression. However, the molecular mechanisms underlying this potential association of the M2 polarization with atherosclerosis regression remain poorly understood. Further, human genetic factors that facilitate these anti-atherogenic processes remain largely unknown. We report that the transcription factor MafB plays pivotal roles in promoting macrophage M2 polarization. Further, MafB promotes cholesterol efflux from macrophage foam cells by directly up-regulating its key cellular mediators. Notably, MafB expression is significantly up-regulated in response to various metabolic and immunological stimuli that promote macrophage M2 polarization or cholesterol efflux, and thereby MafB mediates their beneficial effects, in both liver x receptor (LXR)-dependent and independent manners. In contrast, MafB is strongly down-regulated upon elevated pro-inflammatory signaling or by pro-inflammatory and pro-atherogenic microRNAs, miR-155 and miR-33. Using an integrative systems biology approach, we also revealed that M2 polarization and cholesterol efflux do not necessarily represent inter-dependent events, but MafB is broadly involved in both the processes. These findings highlight physiological protective roles that MafB may play against atherosclerosis progression.

A Helicobacter pylori Homolog of Eukaryotic Flotillin Is Involved in Cholesterol Accumulation, Epithelial Cell Responses and Host Colonization.

The human pathogen Helicobacter pylori acquires cholesterol from membrane raft domains in eukaryotic cells, commonly known as "lipid rafts." Incorporation of this cholesterol into the H. pylori cell membrane allows the bacterium to avoid clearance by the host immune system and to resist the effects of antibiotics and antimicrobial peptides. The presence of cholesterol in H. pylori bacteria suggested that this pathogen may have cholesterol-enriched domains within its membrane. Consistent with this suggestion, we identified a hypothetical H. pylori protein (HP0248) with homology to the flotillin proteins normally found in the cholesterol-enriched domains of eukaryotic cells. As shown for eukaryotic flotillin proteins, HP0248 was detected in detergent-resistant membrane fractions of H. pylori. Importantly, H. pylori HP0248 mutants contained lower levels of cholesterol than wild-type bacteria (P < 0.01). HP0248 mutant bacteria also exhibited defects in type IV secretion functions, as indicated by reduced IL-8 responses and CagA translocation in epithelial cells (P < 0.05), and were less able to establish a chronic infection in mice than wild-type bacteria (P < 0.05). Thus, we have identified an H. pylori flotillin protein and shown its importance for bacterial virulence. Taken together, the data demonstrate important roles for H. pylori flotillin in host-pathogen interactions. We propose that H. pylori flotillin may be required for the organization of virulence proteins into membrane raft-like structures in this pathogen.

Crosstalk Between Enzyme Matrix Metalloproteinases 2 and 9 and Regulatory T Cell Immunity in the Global Burden of Atherosclerosis.

Changes in immune and inflammatory responses may play a crucial role in the development and progression of atherosclerosis, as an autoimmune, chronic and progressive inflammatory disease. Immunological activity and vascular inflammation during atherosclerosis can be modulated by autoimmune responses against self-antigens, according to changeable risk factors (cholesterol, oxidized low-density lipoprotein (ox-LDL) in the vascular wall, fatty acids, etc.), and accompanied by accumulation of leucocytes and proinflammatory cytokines, which stimulate the transcription of matrix metalloproteinases (MMPs), whose concentration are increased in foam cell-rich regions. Regulatory T cells (Tregs) represent a unique subpopulation of T cells specialized in the regulation of immune response and in the suppression of proatherogenic T cells. The aim of our study was to examine the interactions between the concentration of enzyme matrix metalloproteinases 2 and 9 (MMP-2 and 9) in urine and the percentage of Tregs in peripheral blood of two groups of patients: with carotid artery stenosis (CAS), undergoing surgery and with mild atherosclerosis (A) from general practice. The method of enzyme immunoassay (ELISA) was used to determine enzyme MMP expression, and Tregs was examined by flow cytometric analysis. Our data have showed a large increase in the enzyme MMP-2 and 9 in the urine of CAS and A patients in comparison with healthy controls and indicated this method as an easy marker for the monitoring of the development of atherosclerosis. Simultaneously, the diminished number of Tregs in the same patients pointed the importance of these regulatory mechanisms in the etiopathogenesis of atherosclerosis and possible Tregs-mediated therapy.

Remnant Cholesterol Elicits Arterial Wall Inflammation and a Multilevel Cellular Immune Response in Humans.

OBJECTIVE: Mendelian randomization studies revealed a causal role for remnant cholesterol in cardiovascular disease. Remnant particles accumulate in the arterial wall, potentially propagating local and systemic inflammation. We evaluated the impact of remnant cholesterol on arterial wall inflammation, circulating monocytes, and bone marrow in patients with familial dysbetalipoproteinemia (FD). APPROACH AND RESULTS: Arterial wall inflammation and bone marrow activity were measured using 18F-FDG PET/CT. Monocyte phenotype was assessed with flow cytometry. The correlation between remnant levels and hematopoietic activity was validated in the CGPS (Copenhagen General Population Study). We found a 1.2-fold increase of 18F-FDG uptake in the arterial wall in patients with FD (n=17, age 60±8 years, remnant cholesterol: 3.26 [2.07-5.71]) compared with controls (n=17, age 61±8 years, remnant cholesterol 0.29 [0.27-0.40]; P<0.001). Monocytes from patients with FD showed increased lipid accumulation (lipid-positive monocytes: Patients with FD 92% [86-95], controls 76% [66-81], P=0.001, with an increase in lipid droplets per monocyte), and a higher expression of surface integrins (CD11b, CD11c, and CD18). Patients with FD also exhibited monocytosis and leukocytosis, accompanied by a 1.2-fold increase of 18F-FDG uptake in bone marrow. In addition, we found a strong correlation between remnant levels and leukocyte counts in the CGPS (n=103 953, P for trend 5×10-276). In vitro experiments substantiated that remnant cholesterol accumulates in human hematopoietic stem and progenitor cells coinciding with myeloid skewing. CONCLUSIONS: Patients with FD have increased arterial wall and cellular inflammation. These findings imply an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to the increased cardiovascular disease risk in patients with FD.

Immune oxysterols: Role in mycobacterial infection and inflammation.

Infection remains an important cause of morbidity and mortality. Natural defenses to infection are mediated by intrinsic/innate and adaptive immune responses. While our understanding is considerable it is incomplete and emerging areas of research such as those related to the immune-metabolic axis are only beginning to be appreciated. There is increasing evidence showing a connection between immune signalling and the regulation of sterol and fatty acid metabolism. In particular, metabolic intermediates of cholesterol biosynthesis and its oxidized metabolites (oxysterols) have been shown to regulate adaptive immunity and inflammation and for innate immune signalling to regulate the dynamics of cholesterol synthesis and homeostasis. The side-chain oxidized oxysterols, 25-hydroxycholesterol (25HC) and vitamin D metabolites (vitamin D3 and vitamin D2), are now known to impart physiologically profound effects on immune responses. Macrophages play a frontline role in this process connecting immunity, infection and lipid biology, and collaterally are a central target for infection by a wide range of pathogens including viruses and bacteria, especially intracellular bacteria such as mycobacteria. Clinical manifestations of disease severity in the infected host are likely to pay tribute to perturbations of the metabolic-immune phenomena found in lymphocytes and myeloid cells. Historically and consistent with this notion, vitamin D based oxysterols have had a long association with promoting clinical improvements to patients infected with Mycobacterium tuberculosis. Hence understanding the role of early metabolic mediators of inflammatory responses to infection in particular oxysterols, will aid in the development of urgently needed host directed therapeutic and diagnostic design innovation to combat adverse infection outcomes and antibiotic resistance.

Systems Analysis of the Complement-Induced Priming Phase of Liver Regeneration.

Liver regeneration is a well-orchestrated process in the liver that allows mature hepatocytes to reenter the cell cycle to proliferate and replace lost or damaged cells. This process is often impaired in fatty or diseased livers, leading to cirrhosis and other deleterious phenotypes. Prior research has established the role of the complement system and its effector proteins in the progression of liver regeneration; however, a detailed mechanistic understanding of the involvement of complement in regeneration is yet to be established. In this study, we have examined the role of the complement system during the priming phase of liver regeneration through a systems level analysis using a combination of transcriptomic and metabolomic measurements. More specifically, we have performed partial hepatectomy on mice with genetic deficiency in C3, the major component of the complement cascade, and collected their livers at various time points. Based on our analysis, we show that the C3 cascade activates c-fos and promotes the TNF-α signaling pathway, which then activates acute-phase genes such as serum amyloid proteins and orosomucoids. The complement activation also regulates the efflux and the metabolism of cholesterol, an important metabolite for cell cycle and proliferation. Based on our systems level analysis, we provide an integrated model for the complement-induced priming phase of liver regeneration.