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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 6412

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Prof. Dr. Athanasia Mouzaki

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Division of Hematology, Department of Internal Medicine, University of Patras Medical School, 26504 Patras, Greece
Interests: cellular and molecular immunology; immunohematology; T-cells; cytokines; transcription; HIV-1; autoimmunity
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Dear Colleagues,

In recent years, there have been tremendous developments pertaining to biotechnological methods that have made it possible for researchers to identify and better characterize immune system cells and the cytokines they secrete. New cell types and cytokines have been described and new functions have been uncovered, leading to a better understanding of the immune response and how it Is influenced by other physiological systems. Some of this research is being translated into novel immunomodulatory treatments, many of which fall short of the new insights that are emerging from in vitro and animal studies.

For this topic, we invite contributions describing new data on immune cells and cytokines in all areas of molecular, cellular, and clinical immunology.

In particular, we welcome contributions that describe:
(1) new functions of cells and cytokines;
(2) new mechanistic insights into their disease function;
(3) new data for the use of immune cells and cytokines in the diagnosis and treatment of immune diseases.

Review articles are not discouraged, but authors should seek invitation before submission by sending an abstract that describes the content of the proposed review.

Prof. Dr. Athanasia Mouzaki
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (7 papers)

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Research

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18 pages, 2708 KiB

Open AccessArticle

HLA-DR Expression in Natural Killer Cells Marks Distinct Functional States, Depending on Cell Differentiation Stage

by Sofya A. Kust, Maria O. Ustiuzhanina, Maria A. Streltsova, Pavel V. Shelyakin, Maxim A. Kryukov, Gennady V. Lutsenko, Anna V. Sudarikova, Ekaterina M. Merzlyak, Olga V. Britanova, Alexandr M. Sapozhnikov and Elena I. Kovalenko

Int. J. Mol. Sci. 2024, 25(9), 4609; https://doi.org/10.3390/ijms25094609 - 23 Apr 2024

Viewed by 228

Abstract

HLA-DR-positive NK cells, found in both healthy individuals and patients with different inflammatory diseases, are characterized as activated cells. However, data on their capacity for IFNγ production or cytotoxic response vary between studies. Thus, more precise investigation is needed of the mechanisms related to the induction of HLA-DR expression in NK cells, their associations with NK cell differentiation stage, and functional or metabolic state. In this work, HLA-DR-expressing NK cell subsets were investigated using transcriptomic analysis, metabolic activity assays, and analysis of intercellular signaling cascades. We demonstrated that HLA-DR⁺CD56^bright NK cells were characterized by a proliferative phenotype, while HLA-DR⁺CD56^dim NK cells exhibited features of adaptive cells and loss of inhibitory receptors with increased expression of MHC class II trans-activator CIITA. The activated state of HLA-DR-expressing NK cells was confirmed by higher levels of ATP and mitochondrial mass observed in this subset compared to HLA-DR⁻ cells, both ex vivo and after stimulation in culture. We showed that HLA-DR expression in NK cells in vitro can be induced both through stimulation by exogenous IL-2 and IL-21, as well as through auto-stimulation by NK-cell-produced IFNγ. At the intracellular level, HLA-DR expression depended on the activation of STAT3- and ERK1/2-mediated pathways, with subsequent activation of isoform 3 of the transcription factor CIITA. The obtained results broaden the knowledge about HLA-DR-positive NK cell appearance, diversity, and functions, which might be useful in terms of understanding the role of this subset in innate immunity and assessing their possible implications in NK cell-based therapy. Full article

(This article belongs to the Special Issue Advanced Research on Immune Cells and Cytokines)

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28 pages, 5672 KiB

Open AccessArticle

Primary Human M2 Macrophage Subtypes Are Distinguishable by Aqueous Metabolite Profiles

by Amanda L. Fuchs, Stephanann M. Costello, Sage M. Schiller, Brian P. Tripet and Valérie Copié

Int. J. Mol. Sci. 2024, 25(4), 2407; https://doi.org/10.3390/ijms25042407 - 18 Feb 2024

Viewed by 765

Abstract

The complexity of macrophage (MΦ) plasticity and polarization states, which include classically activated pro-inflammatory (M1) and alternatively activated anti-inflammatory (M2) MΦ phenotypes, is becoming increasingly appreciated. Within the M2 MΦ polarization state, M2a, M2b, M2c, and M2d MΦ subcategories have been defined based on their expression of specific cell surface receptors, secreted cytokines, and specialized immune effector functions. The importance of immunometabolic networks in mediating the function and regulation of MΦ immune responses is also being increasingly recognized, although the exact mechanisms and extent of metabolic modulation of MΦ subtype phenotypes and functions remain incompletely understood. In this study, proton (¹H) nuclear magnetic resonance (NMR) metabolomics was employed to determine the polar metabolomes of M2 MΦ subtypes and to investigate the relationship between aqueous metabolite profiles and M2 MΦ functional phenotypes. Results from this study demonstrate that M2a MΦs are most distinct from M2b, M2c, and M2d MΦ subtypes, and that M2b MΦs display several metabolic traits associated with an M1-like MΦ phenotype. The significance of metabolome differences for metabolites implicated in glycolysis, the tricarboxylic acid (TCA) cycle, phospholipid metabolism, and creatine–phosphocreatine cycling is discussed. Altogether, this study provides biochemical insights into the role of metabolism in mediating the specialized effector functions of distinct M2 MΦ subtypes and supports the concept of a continuum of macrophage activation states rather than two well-separated and functionally distinct M1/M2 MΦ classes, as originally proposed within a classical M1/M2 MΦ framework. Full article

(This article belongs to the Special Issue Advanced Research on Immune Cells and Cytokines)

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14 pages, 967 KiB

Open AccessArticle

Involvement of M1-Activated Macrophages and Perforin/Granulysin Expressing Lymphocytes in IgA Vasculitis Nephritis

by Gordana Laskarin, Emina Babarovic, Nastasia Kifer, Stela Bulimbasic, Mario Sestan, Martina Held, Marijan Frkovic, Alenka Gagro, Marijana Coric and Marija Jelusic

Int. J. Mol. Sci. 2024, 25(4), 2253; https://doi.org/10.3390/ijms25042253 - 13 Feb 2024

Viewed by 657

Abstract

We investigated the polarisation of CD68+ macrophages and perforin and granulysin distributions in kidney lymphocyte subsets of children with IgA vasculitis nephritis (IgAVN). Pro-inflammatory macrophage (M)1 (CD68/iNOS) or regulatory M2 (CD68/arginase-1) polarisation; spatial arrangement of macrophages and lymphocytes; and perforin and granulysin distribution in CD3+ and CD56+ cells were visulaised using double-labelled immunofluorescence. In contrast to the tubules, iNOS+ cells were more abundant than the arginase-1+ cells in the glomeruli. CD68+ macrophage numbers fluctuated in the glomeruli and were mostly labelled with iNOS. CD68+/arginase-1+ cells are abundant in the tubules. CD56+ cells, enclosed by CD68+ cells, were more abundant in the glomeruli than in the tubuli, and co-expressed NKp44. The glomerular and interstitial/intratubular CD56+ cells express perforin and granulysin, respectively. The CD3+ cells did not express perforin, while a minority expressed granulysin. Innate immunity, represented by M1 macrophages and CD56+ cells rich in perforin and granulysin, plays a pivotal role in the acute phase of IgAVN. Full article

(This article belongs to the Special Issue Advanced Research on Immune Cells and Cytokines)

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15 pages, 2888 KiB

Open AccessArticle

Interferon-β Overexpression in Adipose Tissue-Derived Stem Cells Induces HepG2 and Macrophage Cell Death in Liver Tumor Organoids via Induction of TNF-Related Apoptosis-Inducing Ligand Expression

by Yongdae Yoon, Chang Wan Kim, Moon Young Kim, Soon Koo Baik, Pil Young Jung and Young Woo Eom

Int. J. Mol. Sci. 2024, 25(2), 1325; https://doi.org/10.3390/ijms25021325 - 22 Jan 2024

Viewed by 912

Abstract

Liver tumor organoids derived from liver tumor tissues and pluripotent stem cells are used for liver tumor research but have several challenges in primary cell isolation and stem cell differentiation. Here, we investigated the potential of HepG2-based liver tumor organoids for screening anticancer drugs by evaluating their responsiveness to IFN-β produced by mesenchymal stem cells (MSCs). Liver tumor organoids were prepared in three days on Matrigel using HepG2, primary liver sinusoidal epithelial cells (LSECs), LX-2 human hepatic stellate cells, and THP-1-derived macrophages at a ratio of 4:4:1:1, with 10⁵ total cells. Hepatocyte-related and M2 macrophage-associated genes increased in liver tumor organoids. IFN-β treatment decreased the viability of liver tumor organoids and increased M1 macrophage marker expression (i.e., TNF-α and iNOS) and TRAIL. TRAIL expression was increased in all four cell types exposed to IFN-β, but cell death was only observed in HepG2 cells and macrophages. Further, MSCs overexpressing IFN-β (ASC-IFN-β) also expressed TRAIL, contributing to the reduced viability of liver tumor organoids. In summary, IFN-β or ASC-IFN-β can induce TRAIL-dependent HepG2 and macrophage cell death in HepG2-based liver tumor organoids, highlighting these liver tumor organoids as suitable for anticancer drug screening and mechanistic studies. Full article

(This article belongs to the Special Issue Advanced Research on Immune Cells and Cytokines)

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20 pages, 5647 KiB

Open AccessArticle

Prolonged Inhibition of the MEK1/2-ERK Signaling Axis Primes Interleukin-1 Beta Expression through Histone 3 Lysine 9 Demethylation in Murine Macrophages

by Rachel Low, Soon-Duck Ha, Nichita Sleapnicov, Parthiv Maneesh and Sung Ouk Kim

Int. J. Mol. Sci. 2023, 24(19), 14428; https://doi.org/10.3390/ijms241914428 - 22 Sep 2023

Viewed by 1098

Abstract

Macrophages undergo different cellular states upon activation that can be hyporesponsive (tolerated) or hyperresponsive (primed or trained) to subsequent stimuli. Epigenetic modifications are known to play key roles in determining these cellular states. However, little is known about the role of signaling pathways that lead to these epigenetic modifications. Here, we examined the effects of various inhibitors targeting key signaling pathways induced by lipopolysaccharide (LPS) on tolerance and priming in murine macrophages. We found that a prolonged inhibition (>18 h) of the mitogen-activated protein kinase (MEK)1/2—extracellular signal-regulated kinase (ERK)1/2 signaling axis reversed tolerance and primed cells in expressing interleukin (IL)-1β and other inflammatory cytokines such as IL-6, tumor necrosis factor (TNF)α, and CXCL10. The ectopic expression of catalytically active and inactive MEK1 mutants suppressed and enhanced IL-1β expression, respectively. A transcriptomic analysis showed that cells primed by the MEK1/2 inhibitor U0126 expressed higher levels of gene sets associated with immune responses and cytokine/chemokine production, but expressed lower levels of genes with cell cycle progression, chromosome organization, and heterochromatin formation than non-primed cells. Of interest, the mRNA expressions of the histone 3 lysine 9 (H3K9) methyltransferase Suv39h1 and the H3K9 methylation reader Cbx5 were substantially suppressed, whereas the H3K9 demethylase Kdm7a was enhanced, suggesting a role of the MEK1/2-ERK signaling axis in H3K9 demethylation. The H3K9 trimethylation levels in the genomic regions of IL-1β, TNFα, and CXCL10 were decreased by U0126. Also, the H3K9 methyltransferase inhibitor BIX01294 mimicked the U0126 training effects and the overexpression of chromobox homolog (CBX)5 prevented the U0126 training effects in both RAW264.7 cells and bone-marrow-derived macrophages. Collectively, these data suggest that the prolonged inhibition of the MEK1/2-ERK signaling axis reverses tolerance and primed macrophages likely through decreasing the H3K9 methylation levels. Full article

(This article belongs to the Special Issue Advanced Research on Immune Cells and Cytokines)

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12 pages, 2762 KiB

Open AccessArticle

Elevation of Metrnβ and Its Association with Disease Activity in Systemic Lupus Erythematosus

by Chen Zhang, Shijie Cai, Ying Li, Xiaoyan Xu, Yonghui Liu, Huaiyu Qiao, Chun-Kwok Wong, Guoqiu Wu, Hui Jin and Xun Gao

Int. J. Mol. Sci. 2023, 24(17), 13607; https://doi.org/10.3390/ijms241713607 - 02 Sep 2023

Viewed by 922

Abstract

Systemic lupus erythematosus (SLE) is an auto-immune disease, the pathogenesis of which remains to be fully addressed. Metrnβ is a novel cytokine involved in the pathogenesis of inflammatory disease, but its regulatory roles in SLE are unclear. We aimed to comprehensively investigate the clinical value of Metrnβ in SLE. A massive elevation of circulating Metrnβ levels was observed in SLE, and patients with an active phase displayed higher Metrnβ concentrations than those with inactive phases. Additionally, we found that Metrnβ expression was positively correlated with clinical indicators of SLE. Longitudinal cytokine and chemokine profiles revealed a disturbed immune response in SLE, with high activity profiles displayed severe pathogenic inflammation, and a positive correlation of the serum Metrnβ with CXCL9, IL10, IL18 and IL1RA was observed as well. Moreover, Metrnβ expressions exhibited an inverse correlation with Treg and B10. Of note, a significant decrease of ILC2 was found in SLE, and there was a negative correlation of Metrnβ with ILC2 as well. Further ROC analysis showed that the area under the curve (AUC) for Metrnβ was 0.8250 (95% CI: 0.7379–0.9121), with a cutoff value of 1131 pg/mL to effectively distinguish SLE patients from healthy controls. Our study herein demonstrated for the first time that Metrnβ values were increased and were immunologically correlated with SLE activity, which could be utilized as an alternative biomarker for the early identification and predicting of the immuno-response of SLE. Full article

(This article belongs to the Special Issue Advanced Research on Immune Cells and Cytokines)

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Review

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13 pages, 905 KiB

Open AccessReview

Immune Status of Individuals with Traumatic Spinal Cord Injury: A Systematic Review and Meta-Analysis

by Ezra Valido, Gabriela Boehl, Jörg Krebs, Jürgen Pannek, Stevan Stojic, Atanas G. Atanasov, Marija Glisic and Jivko Stoyanov

Int. J. Mol. Sci. 2023, 24(22), 16385; https://doi.org/10.3390/ijms242216385 - 16 Nov 2023

Viewed by 1131

Abstract

Individuals with spinal cord injury (SCI) have higher infection rates compared to those without SCI. In this review, the immune status difference between individuals with and without traumatic SCI is investigated by examining their peripheral immune cells and markers. PubMed, Cochrane, EMBASE, and Ovid MEDLINE were searched without language or date restrictions. Studies reporting peripheral immune markers’ concentration and changes in functional capabilities of immune cells that compared individuals with and without SCI were included. Studies with participants with active infection, immune disease, and central nervous system (CNS) immune markers were excluded. The review followed the PRISMA guidelines. Effect estimates were measured by Weighted Mean Difference (WMD) using a random-effects model. Study quality was assessed using the National Heart, Lung, and Blood Institute Quality Assessment Tool. Fifty-four studies (1813 with SCI and 1378 without SCI) contributed to the meta-analysis. Leukocytes (n = 23, WMD 0.78, 95% CI 0.17; 1.38, I² 83%), neutrophils (n = 11, WMD 0.76, 95% CI 0.09; 1.42, I² 89%), C-reactive protein (CRP) (n = 12, WMD 2.25, 95% CI 1.14; 3.56, I² 95%), and IL6 (n = 13, WMD 2.33, 95% CI 1.20; 3.49, I² 97%) were higher in individuals with SCI vs. without SCI. Clinical factors (phase of injury, completeness of injury, sympathetic innervation impairment, age, sex) and study-related factors (sample size, study design, and serum vs. plasma) partially explained heterogeneity. Immune cells exhibited lower functional capability in individuals with SCI vs. those without SCI. Most studies (75.6%) had a moderate risk of bias. The immune status of individuals with SCI differs from those without SCI and is clinically influenced by the phase of injury, completeness of injury, sympathetic innervation impairment, age, and sex. These results provide information that is vital for monitoring and management strategies to effectively improve the immune status of individuals with SCI. Full article

(This article belongs to the Special Issue Advanced Research on Immune Cells and Cytokines)

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