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Immune Cell Regulation during Inflammatory Responses

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

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 40340

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Special Issue Editors

Dr. Jeongho Park

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Guest Editor

College of Veterinary Medicine & Institute of Veterinary Science, Kangwon National University, Chuncheon, Korea
Interests: immunology; viral infection; cytokine; T cell regulation; microbiota; autoimmune disease; inflammation

Dr. Maxime Jacquet

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Guest Editor

Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland
Interests: immunology; immune regulation; liver related diseases; T cells; MAIT cells; inflammation

Special Issue Information

Dear Colleagues,

I am pleased to announce that a Special Issue on the topic “Immune Cell Regulation during Inflammatory Responses” is being prepared for publication in the journal IJMS. The immune system is composed of innate and adaptive immune cells, and the harmonious interaction among various immune cells is indispensable for maintaining homeostasis. However, aberrant inflammation is developed repeatedly during antigenic stimulation in cases of infection or autoimmunity. The aim of this Special Issue is to expand our understanding of immune cell regulation when undesired events are elicited. We encourage our colleagues to contribute to the advancement of immunology through the submission of original papers and reviews on this widely discussed topic: inflammation and immune cell regulation during infectious or autoimmune diseases and tumorigenesis.

Dr. Jeongho Park
Dr. Maxime Jacquet
Guest Editors

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Keywords

immune cell
cytokine
chemokine
inflammation
infection
autoimmunity
immunology

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Published Papers (10 papers)

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Research

Jump to: Review

14 pages, 3299 KiB

Open AccessArticle

Immunorthodontics: Role of HIF-1α in the Regulation of (Peptidoglycan-Induced) PD-L1 Expression in Cementoblasts under Compressive Force

by Jiawen Yong, Sabine Gröger, Joerg Meyle and Sabine Ruf

Int. J. Mol. Sci. 2022, 23(13), 6977; https://doi.org/10.3390/ijms23136977 - 23 Jun 2022

Cited by 5 | Viewed by 1802

Abstract

Patients with periodontitis undergoing orthodontic therapy may suffer from undesired dental root resorption. The purpose of this in vitro study was to investigate the molecular mechanisms resulting in PD-L1 expression of cementoblasts in response to infection with Porphyromonas gingivalis (P. gingivalis) peptidoglycan (PGN) and compressive force (CF), and its interaction with hypoxia-inducible factor (HIF)-1α molecule: The cementoblast (OCCM-30) cells were kinetically infected with various concentrations of P. gingivalis PGN in the presence and absence of CF. Western blotting and RT-qPCR were performed to examine the protein expression of PD-L1 and HIF-1α as well as their gene expression. Immunofluorescence was applied to visualize the localization of these proteins within cells. An HIF-1α inhibitor was added for further investigation of necroptosis by flow cytometry analysis. Releases of soluble GAS-6 were measured by ELISA. P. gingivalis PGN dose dependently stimulated PD-L1 upregulation in cementoblasts at protein and mRNA levels. CF combined with P. gingivalis PGN had synergistic effects on the induction of PD-L1. Blockade of HIF-1α inhibited the P. gingivalis PGN-inducible PD-L1 protein expression under compression, indicating an HIF-1α dependent regulation of PD-L1 induction. Concomitantly, an HIF-1α inhibitor decreased the GAS-6 release in the presence of CF and P. gingivalis PGN co-stimulation. The data suggest that PGN of P. gingivalis participates in PD-L1 up-regulation in cementoblasts. Additionally, the influence of compressive force on P. gingivalis PGN-induced PD-L1 expression occurs in HIF-1α dependently. In this regard, HIF-1α may play roles in the immune response of cementoblasts via immune-inhibitory PD-L1. Our results underline the importance of molecular mechanisms involved in bacteria-induced periodontics and root resorption. Full article

(This article belongs to the Special Issue Immune Cell Regulation during Inflammatory Responses)

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17 pages, 5146 KiB

Open AccessArticle

Hedgehog Signalling Modulates Immune Response and Protects against Experimental Autoimmune Encephalomyelitis

by Alicia Ballester, Adriana Guijarro, Beatriz Bravo, Javier Hernández, Rodolfo Murillas, Marta I. Gallego and Sara Ballester

Int. J. Mol. Sci. 2022, 23(6), 3171; https://doi.org/10.3390/ijms23063171 - 15 Mar 2022

Cited by 8 | Viewed by 2072

Abstract

The Hedgehog (Hh) pathway is essential for the embryonic development and homeostatic maintenance of many adult tissues and organs. It has also been associated with some functions of the innate and adaptive immune system. However, its involvement in the immune response has not been well determined. Here we study the role of Hh signalling in the modulation of the immune response by using the Ptch-1-LacZ^+/− mouse model (hereinafter referred to as ptch^+/−), in which the hemizygous inactivation of Patched-1, the Hh receptor gene, causes the constitutive activation of Hh response genes. The in vitro TCR stimulation of spleen and lymph node (LN) T cells showed increased levels of Th2 cytokines (IL-4 and IL-10) in ptch^+/−cells compared to control cells from wild-type (wt) littermates, suggesting that the Th2 phenotype is favoured by Hh pathway activation. In addition, CD4⁺ cells secreted less IL-17, and the establishment of the Th1 phenotype was impaired in ptch^+/− mice. Consistently, in response to an inflammatory challenge by the induction of experimental autoimmune encephalomyelitis (EAE), ptch^+/− mice showed milder clinical scores and more minor spinal cord damage than wt mice. These results demonstrate a role for the Hh/ptch pathway in immune response modulation and highlight the usefulness of the ptch^+/− mouse model for the study of T-cell-mediated diseases and for the search for new therapeutic strategies in inflammatory diseases. Full article

(This article belongs to the Special Issue Immune Cell Regulation during Inflammatory Responses)

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21 pages, 3648 KiB

Open AccessArticle

Modulatory Effects of Fractalkine on Inflammatory Response and Iron Metabolism of Lipopolysaccharide and Lipoteichoic Acid-Activated THP-1 Macrophages

by Edina Pandur, Kitti Tamási, Ramóna Pap, Gergely Jánosa and Katalin Sipos

Int. J. Mol. Sci. 2022, 23(5), 2629; https://doi.org/10.3390/ijms23052629 - 27 Feb 2022

Cited by 6 | Viewed by 2418

Abstract

Fractalkine (CX3CL1) acts as a chemokine as well as a regulator of iron metabolism. Fractalkine binds CX3CR1, the fractalkine receptor on the surface of monocytes/macrophages regulating different intracellular signalling pathways such as mitogen-activated protein kinase (MAPK), phospholipase C (PLC) and NFκB contributing to the production of pro-inflammatory cytokine synthesis, and the regulation of cell growth, differentiation, proliferation and metabolism. In this study, we focused on the modulatory effects of fractalkine on the immune response and on the iron metabolism of Escherichia coli and Pseudomonas aeruginosa lipopolysaccharides (LPS) and Staphylococcus aureus lipoteichoic acid (LTA) activated THP-1 cells to get a deeper insight into the role of soluble fractalkine in the regulation of the innate immune system. Pro-inflammatory cytokine secretions of the fractalkine-treated, LPS/LTA-treated, and co-treated THP-1 cells were determined using ELISArray and ELISA measurements. We analysed the protein expression levels of signalling molecules regulated by CX3CR1 as well as hepcidin, the major iron regulatory hormone, the iron transporters, the iron storage proteins and mitochondrial iron utilization. The results showed that fractalkine treatment alone did not affect the pro-inflammatory cytokine secretion, but it was proposed to act as a regulator of the iron metabolism of THP-1 cells. In the case of two different LPS and one type of LTA with fractalkine co-treatments, fractalkine was able to alter the levels of signalling proteins (NFκB, PSTAT3, Nrf2/Keap-1) regulating the expression of pro-inflammatory cytokines as well as hepcidin, and the iron storage and utilization of the THP-1 cells. Full article

(This article belongs to the Special Issue Immune Cell Regulation during Inflammatory Responses)

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24 pages, 4338 KiB

Open AccessArticle

Role of S100A8/A9 for Cytokine Secretion, Revealed in Neutrophils Derived from ER-Hoxb8 Progenitors

by Yang Zhou, Justine Hann, Véronique Schenten, Sébastien Plançon, Jean-Luc Bueb, Fabrice Tolle and Sabrina Bréchard

Int. J. Mol. Sci. 2021, 22(16), 8845; https://doi.org/10.3390/ijms22168845 - 17 Aug 2021

Cited by 3 | Viewed by 3146

Abstract

S100A9, a Ca²⁺-binding protein, is tightly associated to neutrophil pro-inflammatory functions when forming a heterodimer with its S100A8 partner. Upon secretion into the extracellular environment, these proteins behave like damage-associated molecular pattern molecules, which actively participate in the amplification of the inflammation process by recruitment and activation of pro-inflammatory cells. Intracellular functions have also been attributed to the S100A8/A9 complex, notably its ability to regulate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. However, the complete functional spectrum of S100A8/A9 at the intracellular level is far from being understood. In this context, we here investigated the possibility that the absence of intracellular S100A8/A9 is involved in cytokine secretion. To overcome the difficulty of genetically modifying neutrophils, we used murine neutrophils derived from wild-type and S100A9^−/− Hoxb8 immortalized myeloid progenitors. After confirming that differentiated Hoxb8 neutrophil-like cells are a suitable model to study neutrophil functions, our data show that absence of S100A8/A9 led to a dysregulation of cytokine secretion after lipopolysaccharide (LPS) stimulation. Furthermore, we demonstrate that S100A8/A9-induced cytokine secretion was regulated by the nuclear factor kappa B (NF-κB) pathway. These results were confirmed in human differentiated HL-60 cells, in which S100A9 was inhibited by shRNAs. Finally, our results indicate that the degranulation process could be involved in the regulation of cytokine secretion by S100A8/A9. Full article

(This article belongs to the Special Issue Immune Cell Regulation during Inflammatory Responses)

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15 pages, 2915 KiB

Open AccessArticle

Alleviation of LPS-Induced Inflammation and Septic Shock by Lactiplantibacillus plantarum K8 Lysates

by Gayoung Kim, Kyeong-Hun Choi, Hangeun Kim and Dae-Kyun Chung

Int. J. Mol. Sci. 2021, 22(11), 5921; https://doi.org/10.3390/ijms22115921 - 31 May 2021

Cited by 8 | Viewed by 3715

Abstract

We previously showed that Lactiplantibacillus plantarum K8 and its cell wall components have immunoregulatory effects. In this study, we demonstrate that pre-treatment of L. plantarum K8 lysates reduced LPS-induced TNF-α production in THP-1 cells by down-regulating the early signals of mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB). The down-regulation of signals may be caused by the induction of negative regulators involved in toll-like receptor (TLR)-mediated signaling. However, co-treatment with high concentrations of L. plantarum K8 lysates and lipopolysaccharide (LPS) activated the late signaling of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and NF-κB pathways and resulted in the induction of absent in melanoma 2 (AIM2) inflammasome-mediated interleukin (IL)-1β secretion. Intraperitoneal injection of L. plantarum K8 lysates in LPS-induced endotoxin shock mice alleviated mortality and reduced serum tumor-necrosis factor (TNF)-α, IL-1β, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. In addition, the mRNA levels of TNF-α, IL-1β, and IL-6 decreased in livers from mice injected with L. plantarum K8 followed by LPS. Hematoxylin and eosin (H&E) staining of the liver showed that the cell size was enlarged by LPS injection and slightly reduced by L. plantarum K8 lysate pre-injection followed by LPS injection. Macrophage infiltration of the liver also decreased in response to the combination injection compared with mice injected with only LPS. Taken together, our results show that although L. plantarum K8 lysates differentially regulated the production of LPS-induced inflammatory cytokines in THP-1 cells, the lysates inhibited overall inflammation in mice. Thus, this study suggests that L. plantarum K8 lysates could be developed as a substance that modulates immune homeostasis by regulating inflammation. Full article

(This article belongs to the Special Issue Immune Cell Regulation during Inflammatory Responses)

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Review

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18 pages, 724 KiB

Open AccessReview

Regulation of CD4⁺ and CD8⁺ T Cell Biology by Short-Chain Fatty Acids and Its Relevance for Autoimmune Pathology

by Carmen Schiweck, Sharmili Edwin Thanarajah, Mareike Aichholzer, Silke Matura, Andreas Reif, Elske Vrieze, Andreas Weigert and Alexander Visekruna

Int. J. Mol. Sci. 2022, 23(15), 8272; https://doi.org/10.3390/ijms23158272 - 27 Jul 2022

Cited by 22 | Viewed by 3618

Abstract

The gut microbiota encodes a broad range of enzymes capable of synthetizing various metabolites, some of which are still uncharacterized. One well-known class of microbiota-derived metabolites are the short-chain fatty acids (SCFAs) such as acetate, propionate, butyrate and valerate. SCFAs have long been considered a mere waste product of bacterial metabolism. Novel results have challenged this long-held dogma, revealing a central role for microbe-derived SCFAs in gut microbiota-host interaction. SCFAs are bacterial signaling molecules that act directly on host T lymphocytes by reprogramming their metabolic activity and epigenetic status. They have an essential biological role in promoting differentiation of (intestinal) regulatory T cells and in production of the anti-inflammatory cytokine interleukin-10 (IL-10). These small molecules can also reach the circulation and modulate immune cell function in remote tissues. In experimental models of autoimmune and inflammatory diseases, such as inflammatory bowel disease, multiple sclerosis or diabetes, a strong therapeutic potential of SCFAs through the modulation of effector T cell function was observed. In this review, we discuss current research activities toward understanding a relevance of microbial SCFA for treating autoimmune and inflammatory pathologies from in vitro to human studies. Full article

(This article belongs to the Special Issue Immune Cell Regulation during Inflammatory Responses)

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16 pages, 757 KiB

Open AccessReview

The Complex Interplay between Vaginal Microbiota, HPV Infection, and Immunological Microenvironment in Cervical Intraepithelial Neoplasia: A Literature Review

by Barbara Gardella, Marianna Francesca Pasquali, Marco La Verde, Stefano Cianci, Marco Torella and Mattia Dominoni

Int. J. Mol. Sci. 2022, 23(13), 7174; https://doi.org/10.3390/ijms23137174 - 28 Jun 2022

Cited by 18 | Viewed by 3688

Abstract

Background: in recent years, many studies were carried out to explore the role of vaginal microbiota in HPV infections and cervical intraepithelial neoplasia (CIN) progression. The aim of this study was to conduct a review of the literature to analyze the interaction between the vaginal microbiota, the CIN, and the immunological response. Methods: we performed a literature search, considering papers published between November 2015 and September 2021. Results: despite significant evidence suggesting a role of vaginal microbiota in the pathogenesis of HPV-related lesions, some studies still struggle to demonstrate this correlation. However, the vaginal microbiota of HPV-positive women shows an increased diversity, combined with a reduced relative abundance of Lactobacillus spp. and a higher pH. In cervical dysplasia progression, a strong association is found with new bacteria, and with the deregulation of pathways and hyperexpression of cytokines leading to chronic inflammation. Conclusions: in HPV progression, there is a strong correlation between potential biomarkers, such as Sneathia and Delftia found in community state types IV and II, and chronic inflammation with cytokine overexpression. Better analysis of these factors could be of use in the prevention of the progression of the disease and, eventually, in new therapeutic strategies. Full article

(This article belongs to the Special Issue Immune Cell Regulation during Inflammatory Responses)

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17 pages, 1636 KiB

Open AccessReview

Pathogenesis and Treatment of Cytokine Storm Induced by Infectious Diseases

by Xi-Dian Tang, Tian-Tian Ji, Jia-Rui Dong, Hao Feng, Feng-Qiang Chen, Xi Chen, Hui-Ying Zhao, De-Kun Chen and Wen-Tao Ma

Int. J. Mol. Sci. 2021, 22(23), 13009; https://doi.org/10.3390/ijms222313009 - 30 Nov 2021

Cited by 40 | Viewed by 10404

Abstract

Cytokine storm is a phenomenon characterized by strong elevated circulating cytokines that most often occur after an overreactive immune system is activated by an acute systemic infection. A variety of cells participate in cytokine storm induction and progression, with profiles of cytokines released during cytokine storm varying from disease to disease. This review focuses on pathophysiological mechanisms underlying cytokine storm induction and progression induced by pathogenic invasive infectious diseases. Strategies for targeted treatment of various types of infection-induced cytokine storms are described from both host and pathogen perspectives. In summary, current studies indicate that cytokine storm-targeted therapies can effectively alleviate tissue damage while promoting the clearance of invading pathogens. Based on this premise, “multi-omics” immune system profiling should facilitate the development of more effective therapeutic strategies to alleviate cytokine storms caused by various diseases. Full article

(This article belongs to the Special Issue Immune Cell Regulation during Inflammatory Responses)

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17 pages, 695 KiB

Open AccessReview

Autoinflammatory Diseases and Cytokine Storms—Imbalances of Innate and Adaptative Immunity

by Annalisa Marcuzzi, Elisabetta Melloni, Giorgio Zauli, Arianna Romani, Paola Secchiero, Natalia Maximova and Erika Rimondi

Int. J. Mol. Sci. 2021, 22(20), 11241; https://doi.org/10.3390/ijms222011241 - 18 Oct 2021

Cited by 18 | Viewed by 4696

Abstract

Innate and adaptive immune responses have a well-known link and represent the distinctive origins of several diseases, many of which may be the consequence of the loss of balance between these two responses. Indeed, autoinflammation and autoimmunity represent the two extremes of a continuous spectrum of pathologic conditions with numerous overlaps in different pathologies. A common characteristic of these dysregulations is represented by hyperinflammation, which is an exaggerated response of the immune system, especially involving white blood cells, macrophages, and inflammasome activation with the hyperproduction of cytokines in response to various triggering stimuli. Moreover, hyperinflammation is of great interest, as it is one of the main manifestations of COVID-19 infection, and the cytokine storm and its most important components are the targets of the pharmacological treatments used to combat COVID-19 damage. In this context, the purpose of our review is to provide a focus on the pathogenesis of autoinflammation and, in particular, of hyperinflammation in order to generate insights for the identification of new therapeutic targets and strategies. Full article

(This article belongs to the Special Issue Immune Cell Regulation during Inflammatory Responses)

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22 pages, 842 KiB

Open AccessReview

Adipokines as Immune Cell Modulators in Multiple Sclerosis

by Merel Rijnsburger, Niek Djuric, Inge A. Mulder and Helga E. de Vries

Int. J. Mol. Sci. 2021, 22(19), 10845; https://doi.org/10.3390/ijms221910845 - 7 Oct 2021

Cited by 14 | Viewed by 3595

Abstract

Multiple sclerosis (MS), a chronic inflammatory and demyelinating disease of the central nervous system (CNS), is a major clinical and societal problem, which has a tremendous impact on the life of patients and their proxies. Current immunomodulatory and anti-inflammatory therapies prove to be relatively effective; however, they fail to concomitantly stop ongoing neurological deterioration and do not reverse acquired disability. The proportion to which genetic and environmental factors contribute to the etiology of MS is still incompletely understood; however, a recent association between MS etiology and obesity was shown, with obesity greatly increasing the risk of developing MS. An altered balance of adipokines, which are white adipose tissue (WAT) hormones, plays an important role in the low-grade chronic inflammation during obesity by their pervasive modification of local and systemic inflammation. Vice versa, inflammatory factors secreted by immune cells affect adipokine function. To explore the role of adipokines in MS pathology, we will here review the reciprocal effects of adipokines and immune cells and summarize alterations in adipokine levels in MS patient cohorts. Finally, we will discuss proof-of-concept studies demonstrating the therapeutic potential of adipokines to target both neuroinflammation and neurodegeneration processes in MS. Full article

(This article belongs to the Special Issue Immune Cell Regulation during Inflammatory Responses)

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