Comparative analysis of neutrophil and monocyte epigenomes

ABSTRACTNeutrophils and monocytes provide a first line of defense against infections as part of the innate immune system. Here we report the integrated analysis of transcriptomic and epigenetic landscapes for circulating monocytes and neutrophils with the aim to enable downstream interpretation and functional validation of key regulatory elements in health and disease. We collected RNA-seq data, ChIP-seq of six histone modifications and of DNA methylation by bisulfite sequencing at base pair resolution from up to 6 individuals per cell type. Chromatin segmentation analyses suggested that monocytes have a higher number of cell-specific enhancer regions (4-fold) compared to neutrophils. This highly plastic epigenome is likely indicative of the greater differentiation potential of monocytes into macrophages, dendritic cells and osteoclasts. In contrast, most of the neutrophil-specific features tend to be characterized by repressed chromatin, reflective of their status as terminally differentiated cells. Enhancers were the regions where most of differences in DNA methylation between cells were observed, with monocyte-specific enhancers being generally hypomethylated. Monocytes show a substantially higher gene expression levels than neutrophils, in line with epigenomic analysis revealing that gene more active elements in monocytes. Our analyses suggest that the overexpression of c-Myc in monocytes and its binding to monocyte-specific enhancers could be an important contributor to these differences. Altogether, our study provides a comprehensive epigenetic chart of chromatin states in primary human neutrophils and monocytes, thus providing a valuable resource for studying the regulation of the human innate immune system.

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Role of Toll-like receptors in liver health and disease

Clinical Science ◽

10.1042/cs20110065 ◽

2011 ◽

Vol 121 (10) ◽

pp. 415-426 ◽

Cited By ~ 48

Author(s):

Ruth Broering ◽

Mengji Lu ◽

Joerg F. Schlaak

Keyword(s):

Immune System ◽

Liver Disease ◽

Innate Immune System ◽

Innate Immune ◽

Toll Like Receptors ◽

Evolutionarily Conserved ◽

Liver Health ◽

Health And Disease ◽

Molecular Patterns

TLRs (Toll-like receptors), as evolutionarily conserved germline-encoded pattern recognition receptors, have a crucial role in early host defence by recognizing so-called PAMPs (pathogen-associated molecular patterns) and may serve as an important link between innate and adaptive immunity. In the liver, TLRs play an important role in the wound healing and regeneration processes, but they are also involved in the pathogenesis and progression of various inflammatory liver diseases, including autoimmune liver disease, alcoholic liver disease, non-alcoholic steatohepatitis, fibrogenesis, and chronic HBV (hepatitis B virus) and HCV (hepatitis C virus) infection. Hepatitis viruses have developed different evading strategies to subvert the innate immune system. Thus recent studies have suggested that TLR-based therapies may represent a promising approach in the treatment in viral hepatitis. The present review focuses on the role of the local innate immune system, and TLRs in particular, in the liver.

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Redundant Catalases Detoxify Phagocyte Reactive Oxygen and Facilitate Histoplasma capsulatum Pathogenesis

Infection and Immunity ◽

10.1128/iai.00173-13 ◽

2013 ◽

Vol 81 (7) ◽

pp. 2334-2346 ◽

Cited By ~ 35

Author(s):

Eric D. Holbrook ◽

Katherine A. Smolnycki ◽

Brian H. Youseff ◽

Chad A. Rappleye

Keyword(s):

Immune System ◽

Innate Immune System ◽

Histoplasma Capsulatum ◽

Reactive Oxygen ◽

Innate Immune ◽

Respiratory Pathogen ◽

Human Neutrophils ◽

Content Type

ABSTRACTHistoplasma capsulatumis a respiratory pathogen that infects phagocytic cells. The mechanisms allowingHistoplasmato overcome toxic reactive oxygen molecules produced by the innate immune system are an integral part ofHistoplasma's ability to survive during infection. To probe the contribution ofHistoplasmacatalases in oxidative stress defense, we created and analyzed the virulence defects of mutants lacking CatB and CatP, which are responsible for extracellular and intracellular catalase activities, respectively. Both CatB and CatP protectedHistoplasmafrom peroxide challengein vitroand from antimicrobial reactive oxygen produced by human neutrophils and activated macrophages. Optimal protection required both catalases, as the survival of a double mutant lacking both CatB and CatP was lower than that of single-catalase-deficient cells. Although CatB contributed to reactive oxygen species defensesin vitro, CatB was dispensable for lung infection and extrapulmonary disseminationin vivo. Loss of CatB from a strain also lacking superoxide dismutase (Sod3) did not further reduce the survival ofHistoplasmayeasts. Nevertheless, some catalase function was required for pathogenesis since simultaneous loss of both CatB and CatP attenuatedHistoplasmavirulencein vivo. These results demonstrate thatHistoplasma's dual catalases comprise a system that enablesHistoplasmato efficiently overcome the reactive oxygen produced by the innate immune system.

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Epilogue: The Innate Immune System: A Global Player in Health and Disease

Damage-Associated Molecular Patterns in Human Diseases ◽

10.1007/978-3-319-78655-1_6 ◽

2018 ◽

pp. 109-109

Author(s):

Walter Gottlieb Land

Keyword(s):

Immune System ◽

Innate Immune System ◽

Innate Immune ◽

System A ◽

Global Player ◽

Health And Disease

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Methylome-wide association study of antidepressant use in Generation Scotland and the Netherlands Twin Register implicates the innate immune system

Molecular Psychiatry ◽

10.1038/s41380-021-01412-7 ◽

2021 ◽

Author(s):

Miruna C. Barbu ◽

Floris Huider ◽

Archie Campbell ◽

Carmen Amador ◽

Mark J. Adams ◽

...

Keyword(s):

Mental Health ◽

Dna Methylation ◽

Immune System ◽

Innate Immune System ◽

Meta Analysis ◽

Mental Health Disorders ◽

Innate Immune ◽

Generation Scotland ◽

Antidepressant Use ◽

Health Disorders

AbstractAntidepressants are an effective treatment for major depressive disorder (MDD), although individual response is unpredictable and highly variable. Whilst the mode of action of antidepressants is incompletely understood, many medications are associated with changes in DNA methylation in genes that are plausibly linked to their mechanisms. Studies of DNA methylation may therefore reveal the biological processes underpinning the efficacy and side effects of antidepressants. We performed a methylome-wide association study (MWAS) of self-reported antidepressant use accounting for lifestyle factors and MDD in Generation Scotland (GS:SFHS, N = 6428, EPIC array) and the Netherlands Twin Register (NTR, N = 2449, 450 K array) and ran a meta-analysis of antidepressant use across these two cohorts. We found ten CpG sites significantly associated with self-reported antidepressant use in GS:SFHS, with the top CpG located within a gene previously associated with mental health disorders, ATP6V1B2 (β = −0.055, pcorrected = 0.005). Other top loci were annotated to genes including CASP10, TMBIM1, MAPKAPK3, and HEBP2, which have previously been implicated in the innate immune response. Next, using penalised regression, we trained a methylation-based score of self-reported antidepressant use in a subset of 3799 GS:SFHS individuals that predicted antidepressant use in a second subset of GS:SFHS (N = 3360, β = 0.377, p = 3.12 × 10−11, R2 = 2.12%). In an MWAS analysis of prescribed selective serotonin reuptake inhibitors, we showed convergent findings with those based on self-report. In NTR, we did not find any CpGs significantly associated with antidepressant use. The meta-analysis identified the two CpGs of the ten above that were common to the two arrays used as being significantly associated with antidepressant use, although the effect was in the opposite direction for one of them. Antidepressants were associated with epigenetic alterations in loci previously associated with mental health disorders and the innate immune system. These changes predicted self-reported antidepressant use in a subset of GS:SFHS and identified processes that may be relevant to our mechanistic understanding of clinically relevant antidepressant drug actions and side effects.

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Current Understanding of the Neutrophil Transcriptome in Health and Disease

Cells ◽

10.3390/cells10092406 ◽

2021 ◽

Vol 10 (9) ◽

pp. 2406

Author(s):

Luke W. Garratt

Keyword(s):

Immune System ◽

Transcriptional Activity ◽

Current Knowledge ◽

Innate Immune ◽

Human Neutrophils ◽

Leukocyte Population ◽

Research Priority ◽

Single Cell Rna Sequencing ◽

Health And Disease ◽

Expression Activity

Neutrophils are key cells of the innate immune system. It is now understood that this leukocyte population is diverse in both the basal composition and functional plasticity. Underlying this plasticity is a post-translational framework for rapidly achieving early activation states, but also a transcriptional capacity that is becoming increasingly recognized by immunologists. Growing interest in the contribution of neutrophils to health and disease has resulted in more efforts to describe their transcriptional activity. Whilst initial efforts focused predominantly on understanding the existing biology, investigations with advanced methods such as single cell RNA sequencing to understand interactions of the entire immune system are revealing higher flexibility in neutrophil transcription than previously thought possible and multiple transition states. It is now apparent that neutrophils utilise many forms of RNA in the regulation of their function. This review collates current knowledge on the nuclei structure and gene expression activity of human neutrophils across homeostasis and disease, before highlighting knowledge gaps that are research priority areas.

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Yersinia pestis Two-Component Gene Regulatory Systems Promote Survival in Human Neutrophils

Infection and Immunity ◽

10.1128/iai.00718-09 ◽

2009 ◽

Vol 78 (2) ◽

pp. 773-782 ◽

Cited By ~ 50

Author(s):

Jason L. O'Loughlin ◽

Justin L. Spinner ◽

Scott A. Minnich ◽

Scott D. Kobayashi

Keyword(s):

Immune System ◽

Yersinia Pestis ◽

Innate Immune System ◽

Intracellular Survival ◽

Innate Immune ◽

Human Neutrophils ◽

Regulatory Systems ◽

Two Component ◽

Gene Regulatory ◽

Component Gene

ABSTRACT Human polymorphonuclear leukocytes (PMNs, or neutrophils) are the most abundant innate immune cell and kill most invading bacteria through combined activities of reactive oxygen species (ROS) and antimicrobial granule constituents. Pathogens such as Yersinia pestis resist destruction by the innate immune system and are able to survive in macrophages and neutrophils. The specific molecular mechanisms used by Y. pestis to survive following phagocytosis by human PMNs are incompletely defined. To gain insight into factors that govern Y. pestis intracellular survival in neutrophils, we inactivated 25 two-component gene regulatory systems (TCSs) with known or inferred function and assessed susceptibility of these mutant strains to human PMN granule extracts. Y. pestis strains deficient for PhoPQ, KdpED, CheY, CvgSY, and CpxRA TCSs were selected for further analysis, and all five strains were altered for survival following interaction with PMNs. Of these five strains, only Y. pestis ΔphoPQ demonstrated global sensitivity to a panel of seven individual neutrophil antimicrobial peptides and serine proteases. Notably, Y. pestis ΔphoPQ was deficient for intracellular survival in PMNs. Iterative analysis with Y. pestis strains lacking the PhoP-regulated genes ugd and pmrK indicated that the mechanism most likely responsible for increased resistance to killing is 4-amino-4-deoxy-l-arabinose modification of lipid A. Together, the data provide new information about Y. pestis evasion of the innate immune system.

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Neutrophil extracellular traps and their role in health and disease

South African Journal of Science ◽

10.17159/sajs.2016/20150072 ◽

2016 ◽

Vol Volume 112 (Number 1/2) ◽

Cited By ~ 6

Author(s):

Jan G. Nel ◽

Annette J. Theron ◽

Roger Pool ◽

Chrisna Durandt ◽

Gregory R. Tintinger ◽

...

Keyword(s):

Immune System ◽

Innate Immune System ◽

Neutrophil Extracellular Traps ◽

Limited Range ◽

Innate Immune ◽

Microbial Pathogens ◽

Alternative Mechanism ◽

Viral Pathogens ◽

Extracellular Traps ◽

Health And Disease

Abstract The human innate immune system is indispensable for protection against potentially invasive microbial and viral pathogens, either neutralising them or containing their spread until effective mobilisation of the slower, adaptive (specific), immune response. Until fairly recently, it was believed that the human innate immune system possessed minimal discriminatory activity in the setting of a rather limited range of microbicidal or virucidal mechanisms. However, recent discoveries have revealed that the innate immune system possesses an array of novel pathogen recognition mechanisms, as well as a resourceful and effective alternative mechanism of phagocyte (predominantly neutrophil)-mediated, anti-infective activity known as NETosis. The process of NETosis involves an unusual type of programmed, purposeful cell death, resulting in the extracellular release of a web of chromatin heavily impregnated with antimicrobial proteins. These structures, known as neutrophil extracellular traps (NETs), immobilise and contribute to the eradication of microbial pathogens, ensuring that the anti-infective potential of neutrophils is sustained beyond the lifespan of these cells. The current review is focused on the mechanisms of NETosis and the role of this process in host defence. Other topics reviewed include the potential threats to human health posed by poorly controlled, excessive formation of NETs, specifically in relation to development of autoimmune and cardiovascular diseases, as well as exacerbation of acute and chronic inflammatory disorders of the airways.

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Neutrophil Extracellular Traps in the Second Decade

Journal of Innate Immunity ◽

10.1159/000489829 ◽

2018 ◽

Vol 10 (5-6) ◽

pp. 414-421 ◽

Cited By ~ 62

Author(s):

Volker Brinkmann

Keyword(s):

Immune System ◽

Innate Immune System ◽

Neutrophil Extracellular Traps ◽

Innate Immune ◽

Pathophysiological Mechanisms ◽

Extracellular Traps ◽

Concise Overview ◽

Health And Disease ◽

The Right

Nearly 15 years after the first description of neutrophil extracellular traps (NETs), our knowledge concerning this structure has expanded considerably. Initially, NETs were considered solely an elaborate function of the innate immune system to combat invading microorganisms. Successively it became clear that NETs have farther-reaching capabilities. They are involved in a series of pathophysiological mechanisms ranging from inflammation to thrombosis where they fulfill essential functions when produced at the right site and the right time but can have a serious impact when generation or clearance of NETs is inadequately controlled. This review provides a concise overview on the far-reaching functions of NETs in health and disease.

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Nutrition Regulates Innate Immunity in Health and Disease

Annual Review of Nutrition ◽

10.1146/annurev-nutr-120919-094440 ◽

2020 ◽

Vol 40 (1) ◽

pp. 189-219 ◽

Cited By ~ 1

Author(s):

Samuel Philip Nobs ◽

Niv Zmora ◽

Eran Elinav

Keyword(s):

Innate Immunity ◽

Immune System ◽

Gut Microbiota ◽

Innate Immune System ◽

Nutrient Content ◽

Allergic Diseases ◽

Innate Immune ◽

Nutrient Timing ◽

Cardiometabolic Disorders ◽

Health And Disease

Nutrient content and nutrient timing are considered key regulators of human health and a variety of diseases and involve complex interactions with the mucosal immune system. In particular, the innate immune system is emerging as an important signaling hub that modulates the response to nutritional signals, in part via signaling through the gut microbiota. In this review we elucidate emerging evidence that interactions between innate immunity and diet affect human metabolic health and disease, including cardiometabolic disorders, allergic diseases, autoimmune disorders, infections, and cancers. Furthermore, we discuss the potential modulatory effects of the gut microbiota on interactions between the immune system and nutrition in health and disease, namely how it relays nutritional signals to the innate immune system under specific physiological contexts. Finally, we identify key open questions and challenges to comprehensively understanding the intersection between nutrition and innate immunity and how potential nutritional, immune, and microbial therapeutics may be developed into promising future avenues of precision treatment.

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