Molecular Mechanisms of Leukocyte Migration and Its Potential Targeting—Lessons Learned From MKL1/SRF-Related Primary Immunodeficiency Diseases

Megakaryoblastic leukemia 1 (MKL1) deficiency is one of the most recently discovered primary immunodeficiencies (PIDs) caused by cytoskeletal abnormalities. These immunological “actinopathies” primarily affect hematopoietic cells, resulting in defects in both the innate immune system (phagocyte defects) and adaptive immune system (T-cell and B-cell defects). MKL1 is a transcriptional coactivator that operates together with serum response factor (SRF) to regulate gene transcription. The MKL/SRF pathway has been originally described to have important functions in actin regulation in cells. Recent results indicate that MKL1 also has very important roles in immune cells, and that MKL1 deficiency results in an immunodeficiency affecting the migration and function of primarily myeloid cells such as neutrophils. Interestingly, several actinopathies are caused by mutations in genes which are recognized MKL(1/2)-dependent SRF-target genes, namely ACTB, WIPF1, WDR1, and MSN. Here we summarize these and related (ARPC1B) actinopathies and their effects on immune cell function, especially focusing on their effects on leukocyte adhesion and migration. Furthermore, we summarize recent therapeutic efforts targeting the MKL/SRF pathway in disease.

Download Full-text

The Adaptive Immune System in Multiple Sclerosis: An Estrogen-Mediated Point of View

Cells ◽

10.3390/cells8101280 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1280 ◽

Cited By ~ 2

Author(s):

Alessandro Maglione ◽

Simona Rolla ◽

Stefania Federica De Mercanti ◽

Santina Cutrupi ◽

Marinella Clerico

Keyword(s):

Multiple Sclerosis ◽

Immune System ◽

Molecular Mechanisms ◽

Immune Cell ◽

Adaptive Immune System ◽

Cell Types ◽

Point Of View ◽

Adaptive Immune ◽

Future Path

Multiple sclerosis (MS) is a chronic central nervous system inflammatory disease that leads to demyelination and neurodegeneration. The third trimester of pregnancy, which is characterized by high levels of estrogens, has been shown to be associated with reduced relapse rates compared with the rates before pregnancy. These effects could be related to the anti-inflammatory properties of estrogens, which orchestrate the reshuffling of the immune system toward immunotolerance to allow for fetal growth. The action of these hormones is mediated by the transcriptional regulation activity of estrogen receptors (ERs). Estrogen levels and ER expression define a specific balance of immune cell types. In this review, we explore the role of estradiol (E2) and ERs in the adaptive immune system, with a focus on estrogen-mediated cellular, molecular, and epigenetic mechanisms related to immune tolerance and neuroprotection in MS. The epigenome dynamics of immune systems are described as key molecular mechanisms that act on the regulation of immune cell identity. This is a completely unexplored field, suggesting a future path for more extensive research on estrogen-induced coregulatory complexes and molecular circuitry as targets for therapeutics in MS.

Download Full-text

Modulation of Immunity and Inflammation by the Mineralocorticoid Receptor and Aldosterone

BioMed Research International ◽

10.1155/2015/652738 ◽

2015 ◽

Vol 2015 ◽

pp. 1-14 ◽

Cited By ~ 22

Author(s):

N. Muñoz-Durango ◽

A. Vecchiola ◽

L. M. Gonzalez-Gomez ◽

F. Simon ◽

C. A. Riedel ◽

...

Keyword(s):

Immune System ◽

Mineralocorticoid Receptor ◽

Molecular Mechanisms ◽

Cell Function ◽

Immune Cell ◽

Inflammatory Diseases ◽

Scientific Work ◽

Proinflammatory Mediators ◽

Electrolyte Homeostasis

The mineralocorticoid receptor (MR) is a ligand dependent transcription factor. MR has been traditionally associated with the control of water and electrolyte homeostasis in order to keep blood pressure through aldosterone activation. However, there is growing evidence indicating that MR expression is not restricted to vascular and renal tissues, as it can be also expressed by cells of the immune system, where it responds to stimulation or antagonism, controlling immune cell function. On the other hand, aldosterone also has been associated with proinflammatory immune effects, such as the release of proinflammatory cytokines, generating oxidative stress and inducing fibrosis. The inflammatory participation of MR and aldosterone in the cardiovascular disease suggests an association with alterations in the immune system. Hypertensive patients show higher levels of proinflammatory mediators that can be modulated by MR antagonism. Although these proinflammatory properties have been observed in other autoimmune and chronic inflammatory diseases, the cellular and molecular mechanisms that mediate these effects remain unknown. Here we review and discuss the scientific work aimed at determining the immunological role of MR and aldosterone in humans, as well as animal models.

Download Full-text

Cellular and metabolic mechanisms of nutrient actions in immune function

Nutrition and Diabetes ◽

10.1038/s41387-021-00162-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Philip Newsholme

Keyword(s):

Amino Acids ◽

Fatty Acids ◽

Vitamin D ◽

Immune System ◽

Cell Function ◽

Immune Cell ◽

Cell Structure ◽

Nutritional Intervention ◽

Immune Cell Function ◽

And Function

AbstractVarious nutrients can change cell structure, cellular metabolism, and cell function which is particularly important for cells of the immune system as nutrient availability is associated with the activation and function of diverse immune subsets. The most important nutrients for immune cell function and fate appear to be glucose, amino acids, fatty acids, and vitamin D. This perspective will describe recently published information describing the mechanism of action of prominent nutritional intervention agents where evidence exists as to their action and potency.

Download Full-text

Neuroinflammation and Its Impact on the Pathogenesis of COVID-19

Frontiers in Medicine ◽

10.3389/fmed.2021.745789 ◽

2021 ◽

Vol 8 ◽

Author(s):

Mohammed M. Almutairi ◽

Farzane Sivandzade ◽

Thamer H. Albekairi ◽

Faleh Alqahtani ◽

Luca Cucullo

Keyword(s):

Immune System ◽

Molecular Mechanisms ◽

Potential Role ◽

Immune Cell ◽

Clinical Manifestations ◽

Cell Infiltration ◽

Cellular Mechanisms ◽

Cytokine Levels

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical manifestations of COVID-19 include dry cough, difficult breathing, fever, fatigue, and may lead to pneumonia and respiratory failure. There are significant gaps in the current understanding of whether SARS-CoV-2 attacks the CNS directly or through activation of the peripheral immune system and immune cell infiltration. Although the modality of neurological impairments associated with COVID-19 has not been thoroughly investigated, the latest studies have observed that SARS-CoV-2 induces neuroinflammation and may have severe long-term consequences. Here we review the literature on possible cellular and molecular mechanisms of SARS-CoV-2 induced-neuroinflammation. Activation of the innate immune system is associated with increased cytokine levels, chemokines, and free radicals in the SARS-CoV-2-induced pathogenic response at the blood-brain barrier (BBB). BBB disruption allows immune/inflammatory cell infiltration into the CNS activating immune resident cells (such as microglia and astrocytes). This review highlights the molecular and cellular mechanisms involved in COVID-19-induced neuroinflammation, which may lead to neuronal death. A better understanding of these mechanisms will help gain substantial knowledge about the potential role of SARS-CoV-2 in neurological changes and plan possible therapeutic intervention strategies.

Download Full-text

Triptolide Modulates the Expression of Inflammation-Associated lncRNA-PACER and lincRNA-p21 in Mycobacterium tuberculosis–Infected Monocyte-Derived Macrophages

Frontiers in Pharmacology ◽

10.3389/fphar.2021.618462 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ousman Tamgue ◽

Julius Ebua Chia ◽

Frank Brombacher

Keyword(s):

Mycobacterium Tuberculosis ◽

Target Genes ◽

Cell Function ◽

Immune Cell ◽

Biological Activities ◽

Target Cells ◽

Dependent Manner ◽

Direct Targeting ◽

Non Coding Rnas ◽

Alamarblue Assay

Triptolide is a diterpene triepoxide, which performs its biological activities via mechanisms including induction of apoptosis, targeting of pro-inflammatory cytokines, and reshaping of the epigenetic landscape of target cells. However, the targeting of long non-coding RNAs (lncRNAs) by triptolide has not yet been investigated, despite their emerging roles as key epigenetic regulators of inflammation and immune cell function during Mycobacterium tuberculosis (Mtb) infection. Hence, we investigated whether triptolide targets inflammation-associated lncRNA-PACER and lincRNA-p21 and how this targeting associates with Mtb killing within monocyte-derived macrophages (MDMs).Using RT-qPCR, we found that triptolide induced the expression of lincRNA-p21 but inhibited the expression of lncRNA-PACER in resting MDMs in a dose- and time-dependent manner. Moreover, Mtb infection induced the expression of lincRNA-p21 and lncRNA-PACER, and exposure to triptolide before or after Mtb infection led to further increase of Mtb-induced expression of these lncRNAs in MDMs. We further found that contrary to lncRNA-PACER, triptolide time- and dose-dependently upregulated Ptgs-2, which is a proximal gene regulated by lncRNA-PACER. Also, low-concentration triptolide inhibited the expression of cytokine IL-6, a known target of lincRNA-p21. Mtb infection induced the expression of IL-6 and Ptgs-2, and triptolide treatment further increased IL-6 but decreased Ptgs-2 expression in Mtb-infected MDMs. The inverse relation between the expression of these lncRNAs and their target genes is concordant with the conception that these lncRNAs mediate, at least partially, the cytotoxic and/or anti-inflammatory activities of triptolide in both resting and activated MDMs. Using the CFU count method, we found that triptolide decreased the intracellular growth of Mtb HN878. The alamarBlue assay showed that this decreased Mtb HN878 growth was not as a result of direct targeting of Mtb HN878 by triptolide, but rather evoking MDMs’ intracellular killing mechanisms which we speculate could include triptolide-induced enhancement of MDMs’ effector killing functions mediated by lncRNA-PACER and lincRNA-p21. Altogether, these results provide proof of the modulation of lncRNA-PACER and lincRNA-p21 expression by triptolide, and a possible link between these lncRNAs, the enhancement of MDMs’ effector killing functions and the intracellular Mtb-killing activities of triptolide. These findings prompt for further investigation of the precise contribution of these lncRNAs to triptolide-induced activities in MDMs.

Download Full-text

Evolution during primary HIV infection does not require adaptive immune selection

10.1101/2020.12.07.20245480 ◽

2020 ◽

Author(s):

David A Swan ◽

Morgane Rolland ◽

Joshua Herbeck ◽

Joshua T Schiffer ◽

Daniel B Reeves

Keyword(s):

Viral Load ◽

Immune System ◽

Hiv Infection ◽

Evolutionary Dynamics ◽

Immune Cell ◽

Adaptive Immune System ◽

Viral Fitness ◽

Immune Cell Population ◽

Adaptive Immune

AbstractModern HIV research depends crucially on both viral sequencing and population measurements. To directly link mechanistic biological processes and evolutionary dynamics during HIV infection, we developed multiple within-host phylodynamic (wi-phy) models of HIV primary infection for comparative validation against viral load and evolutionary dynamics data. The most parsimonious and accurate model required no positive selection, suggesting that the host adaptive immune system reduces viral load, but does not drive observed viral evolution. Rather, random genetic drift primarily dictates fitness changes. These results hold during early infection, and even during chronic infection when selection has been observed, viral fitness distributions are not largely different from in vitro distributions that emerge without adaptive immunity. These results highlight how phylogenetic inference must consider complex viral and immune-cell population dynamics to gain accurate mechanistic insights.One sentence summaryThrough the lens of a unified population and phylodynamic model, current data show the first wave of HIV mutations are not driven by selection by the adaptive immune system.

Download Full-text

Reduction of leucocyte cell surface disulfide bonds during immune activation is dynamic as revealed by a quantitative proteomics workflow (SH-IQ)

Open Biology ◽

10.1098/rsob.180079 ◽

2018 ◽

Vol 8 (9) ◽

pp. 180079

Author(s):

Monika Stegmann ◽

A. Neil Barclay ◽

Clive Metcalfe

Keyword(s):

Immune System ◽

Cell Surface ◽

Immune Activation ◽

Disulfide Bonds ◽

Cell Function ◽

Immune Cell ◽

Surface Proteins ◽

Cell Surface Receptors ◽

Surface Receptors ◽

Pathogen Clearance

Communication through cell surface receptors is crucial for maintaining immune homeostasis, coordinating the immune response and pathogen clearance. This is dependent on the interaction of cell surface receptors with their ligands and requires functionally active conformational states. Thus, immune cell function can be controlled by modulating the structure of either the receptor or the ligand. Reductive cleavage of labile disulfide bonds can mediate such an allosteric change, resulting in modulation of the immune system by a hitherto little studied mechanism. Identifying proteins with labile disulfide bonds and determining the extent of reduction is crucial in elucidating the functional result of reduction. We describe a mass spectrometry-based method—thiol identification and quantitation (SH-IQ)—to identify, quantify and monitor such reduction of labile disulfide bonds in primary cells during immune activation. These results provide the first insight into the extent and dynamics of labile disulfide bond reduction in leucocyte cell surface proteins upon immune activation. We show that this process is thiol oxidoreductase-dependent and mainly affects activatory (e.g. CD132, SLAMF1) and adhesion (CD44, ICAM1) molecules, suggesting a mechanism to prevent over-activation of the immune system and excessive accumulation of leucocytes at sites of inflammation.

Download Full-text

EZH2 function in immune cell development

Biological Chemistry ◽

10.1515/hsz-2019-0436 ◽

2020 ◽

Vol 401 (8) ◽

pp. 933-943 ◽

Cited By ~ 5

Author(s):

Stephen L. Nutt ◽

Christine Keenan ◽

Michaël Chopin ◽

Rhys S. Allan

Keyword(s):

Immune System ◽

Cell Function ◽

Immune Cell ◽

Proliferating Cells ◽

Hematopoietic Stem ◽

Polycomb Repressive Complex 2 ◽

Current State ◽

Core Components ◽

And Function ◽

Cell Cycle Inhibitors

AbstractThe polycomb repressive complex 2 (PRC2) consists of three core components EZH2, SUZ12 and EED. EZH2 catalyzes the methylation of lysine 27 of histone H3, a modification associated with gene silencing. Through gene duplication higher vertebrate genomes also encode a second partially redundant methyltransferase, EZH1. Within the mammalian immune system most research has concentrated on EZH2 which is expressed predominantly in proliferating cells. EZH2 and other PRC2 components are required for hematopoietic stem cell function and lymphocyte development, at least in part by repressing cell cycle inhibitors. At later stages of immune cell differentiation, EZH2 plays essential roles in humoral and cell-mediated adaptive immunity, as well as the maintenance of immune homeostasis. EZH2 is often overactive in cancers, through both gain-of-function mutations and over-expression, an observation that has led to the development and clinical testing of specific EZH2 inhibitors. Such inhibitors may also be of use in inflammatory and autoimmune settings, as EZH2 inhibition dampens the immune response. Here, we will review the current state of understanding of the roles for EZH2, and PRC2 more generally, in the development and function of the immune system.

Download Full-text

The FLUENT study design: investigating immune cell subset and neurofilament changes in patients with relapsing multiple sclerosis treated with fingolimod

Multiple Sclerosis Journal - Experimental Translational and Clinical ◽

10.1177/2055217318819245 ◽

2019 ◽

Vol 5 (1) ◽

pp. 205521731881924 ◽

Cited By ~ 1

Author(s):

Jeffrey A Cohen ◽

Amit Bar-Or ◽

Bruce A C Cree ◽

Yang Mao-Draayer ◽

May H Han ◽

...

Keyword(s):

Multiple Sclerosis ◽

Immune System ◽

Immune Cell ◽

Cell Subset ◽

Adaptive Immune System ◽

Study Cohort ◽

Open Label ◽

Receptor Modulator ◽

Circulating Lymphocytes ◽

B Cell Subsets

Background Fingolimod is a sphingosine 1-phosphate receptor modulator for the treatment of patients with relapsing forms of multiple sclerosis (RMS). Fingolimod sequesters lymphocytes within lymphoid tissue thereby reducing the counts of circulating lymphocytes. However, fingolimod’s effects on the innate and adaptive components of the immune system are incompletely understood. Objective The FLUENT study will investigate temporal changes in circulating immune cell subsets in patients with RMS treated with fingolimod. Secondary objectives include examining the association between anti-John Cunningham virus (JCV) antibody status/index and phenotypic changes in innate and T and B cell subsets in patients on fingolimod therapy, and the association between serum neurofilament levels and clinical outcomes. Methods FLUENT is a prospective, multicenter, two-cohort, nonrandomized, open-label Phase IV study. Cohort 1 will include fingolimod-naïve patients and Cohort 2 will include patients who have received fingolimod 0.5 mg/day continuously for ≥2 years. Changes in the cellular components of the innate and adaptive immune system will be characterized over 12 months. Results The study is ongoing. Conclusion FLUENT may provide evidence for the use of immunologic profiling in predicting efficacy and risk of infection in patients with RMS treated with fingolimod.

Download Full-text

A Commitment to Lineage

Blood ◽

10.1182/blood.v116.21.sci-22.sci-22 ◽

2010 ◽

Vol 116 (21) ◽

pp. SCI-22-SCI-22

Author(s):

Laurie H. Glimcher ◽

Vanja Lazarevic ◽

Joerg Ermann ◽

Wendy Garrett

Keyword(s):

Colorectal Cancer ◽

Immune System ◽

Molecular Mechanisms ◽

T Regulatory Cells ◽

Inflammatory Diseases ◽

Rectal Adenocarcinoma ◽

Adaptive Immune System ◽

T Helper ◽

T Helper 1

Abstract Abstract SCI-22 The transcription factor T-bet, isolated in our laboratory a decade ago, is a master regulator of Type 1 immunity in cells of both the adaptive and innate immune system. In adaptive immunity, T-bet instigates genetic programs in T helper 1 (Th1) cells and is required for production of the hallmark Th1 cytokine IFNg. It simultaneously represses the differentiation of T helper 2 cells and the profibrotic cytokines IL-13 and TGFb. We have recently determined that T-bet is also a repressor of the Th17 genetic program and have established the molecular mechanisms that underpin that function. T-bet also controls the optimal differentiation and function of the cytolytic CD8 cell, and is required for the development of the natural killer T cell. T-bet deficient animals are largely protected from autoimmune/inflammatory diseases such as multiple sclerosis, systemic lupus, type 1 diabetes and inflammatory arthritis, but are susceptible to type 2 driven diseases such as asthma and scleroderma. An exception to this overall rule is our recent discovery that in the absence of an adaptive immune system, the majority of mice lacking T-bet develop a spontaneous ulcerative colitis that progresses to colonic dysplasia and rectal adenocarcinoma. This colitis and inflammation associated colorectal cancer are MyD88 independent, driven by colitogenic flora and ameliorated by treatment with TNF blockade, antibiotics, and transfer of T regulatory cells. This phenotype maps to the T-bet deficient dendritic cell that drives this pro-inflammatory program; selective over-expression of T-bet in DCs was sufficient to reduce colonic inflammation and prevent the progression to neoplasia. The molecular pathogenesis of TRUC colitis and colitis-associated colorectal (caCRC) shares several key features with human caCRC. This model of colitis and colitis-associated colorectal cancer provides opportunities to further understand host-microbial relationships in inflammation and neoplasia and test preventative and therapeutic strategies pre-clinically. The function and mechanism of action of T-bet in the pathogenesis of immune system driven diseases will be discussed. Disclosures: Glimcher: Merck: Consultancy, Patents & Royalties, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Download Full-text