Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Pro-inflammatory and Anti-inflammatory Cytokines in Autoimmune Diseases

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 77314

Share This Special Issue

Special Issue Editor

Prof. Dr. Pio Conti

E-Mail
Guest Editor

Postgraduate Medical School, University of Chieti, Chieti, Italy
Interests: inflammation; innate immunity; cell culture; immunology of infectious diseases; psoriasis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cytokines are immunoregulatory proteins which mediate many pathophysiological states. The increased concentration of cytokines in humans causes local and systemic inflammation, which can even lead to death.

Inflammatory cytokines are proteins that underlie immune-mediated diseases and contribute to the pathogenesis of autoimmune diseases.

In autoimmune diseases, increased levels of pro-inflammatory cytokines have been found in the serum of affected persons, and are positively correlated with disease severity, suggesting that pro-inflammatory cytokines may be a prognostic marker of autoimmune disorders.

The uncontrolled production of the pro-inflammatory cytokines involved in autoimmunity suggests the need to find new therapeutic targets in order to alleviate the disease.

Some anti-inflammatory cytokines have recently been described to suppress inflammation by nonspecific inhibition of several cytokines and chemokines.

These topics are very intricate, and deserve thorough study.

Prof. Pio Conti
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 (10 papers)

Download All Papers

Research

Jump to: Review

15 pages, 2056 KiB

Open AccessArticle

Multifunctional Interleukin-24 Resolves Neuroretina Autoimmunity via Diverse Mechanisms

by Xuan Zhang, Cuiping Hu, Yajie Zhong, Dijie Qiao, Wei Chi, Huangxuan Shen and Waipo Chong

Int. J. Mol. Sci. 2022, 23(19), 11988; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911988 - 09 Oct 2022

Cited by 2 | Viewed by 1392

Abstract

IL-24 is a multifunctional cytokine that regulates both immune cells and epithelial cells. Although its elevation is associated with a number of autoimmune diseases, its tolerogenic properties against autoreactive T cells have recently been revealed in an animal model of central nervous system (CNS) autoimmunity by inhibiting the pathogenic Th17 response. To explore the potential of IL-24 as a therapeutic agent in CNS autoimmunity, we induced experimental autoimmune uveitis (EAU) in wildtype mice and intravitreally injected IL-24 into the inflamed eye after disease onset. We found that the progression of ocular inflammation was significantly inhibited in the IL-24-treated eye when compared to the control eye. More importantly, IL-24 treatment suppressed cytokine production from ocular-infiltrating, pathogenic Th1 and Th17 cells. In vitro experiments confirmed that IL-24 suppressed both Th1 and Th17 differentiation by regulating their master transcription factors T-bet and RORγt, respectively. In addition, we found that intravitreal injection of IL-24 suppressed the production of proinflammatory cytokines and chemokines from the retinas of the EAU-inflamed eyes. This observation appears to be applicable in humans, as IL-24 similarly inhibits human retinal pigment epithelium cells ARPE-19. In conclusion, we report here that IL-24, as a multifunctional cytokine, is capable of resolving ocular inflammation in EAU mice by targeting both uveitogenic T cells and RPE cells. This study sheds new light on IL-24 as a potential therapeutic candidate for autoimmune uveitis. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Cytokines in Autoimmune Diseases)

► Show Figures

Figure 1

17 pages, 1976 KiB

Open AccessArticle

Deficiency of IL-27 Signaling Exacerbates Experimental Autoimmune Uveitis with Elevated Uveitogenic Th1 and Th17 Responses

by Sihan Wu, Rui Ma, Yajie Zhong, Zilin Chen, Hongyan Zhou, Minyi Zhou, Waipo Chong and Jun Chen

Int. J. Mol. Sci. 2021, 22(14), 7517; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147517 - 14 Jul 2021

Cited by 8 | Viewed by 2731

Abstract

Human uveitis is an autoimmune disease of the central nervous system that is characterized by ocular inflammation with the involvement of uveitogenic Th1 and Th17 responses. In experimental autoimmune uveitis (EAU), the animal model for human uveitis, both responses are proven to be critical in disease development. Therefore, targeting both Th1 and Th17 cells has therapeutic implication for disease resolution. IL-27 is a multifunctional cytokine that can either promote or inhibit T cell responses and is implicated in both autoimmune and infectious diseases. The aim of this study is to characterize the role of IL-27/IL-27R signaling in regulating uveitogenic Th1/Th17 responses in EAU. By immunizing IL-27Rα^−/− mice and their wild-type (WT) littermates for EAU, we demonstrated that IL-27 signaling deficiency exacerbated EAU with severe ocular inflammation and impairment of visual function. Furthermore, there was a significant increase in the eye-infiltrating Th1 and Th17 cells in IL-27Rα^−/− EAU mice compared to WT. Their retinal antigen-specific Th1 and Th17 responses were also significantly increased, as represented by the elevation of their signature cytokines, IFN-γ and IL-17A, respectively. We also observed the upregulation of another pathogenic cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), from effector T cells in IL-27Rα^−/− EAU mice. Mechanistic studies confirmed that IL-27 inhibited GM-CSF production from Th17 cells. In addition, the induction of IL-10 producing type 1 regulatory T (Tr1) cells was impaired in IL-27Rα^−/− EAU mice. These results identified that IL-27 signaling plays a suppressive role in EAU by regulating multiple CD4⁺ cell subsets, including the effector Th1 and Th17 cells and the regulatory Tr1 cells. Our findings provide new insights for therapeutic potential in controlling uveitis by enhancing IL-27 signaling. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Cytokines in Autoimmune Diseases)

► Show Figures

Figure 1

11 pages, 2192 KiB

Open AccessArticle

CD1d-Dependent iNKT Cells Control DSS-Induced Colitis in a Mouse Model of IFNγ-Mediated Hyperinflammation by Increasing IL22-Secreting ILC3 Cells

by Hyun Jung Park, Sung Won Lee, Luc Van Kaer and Seokmann Hong

Int. J. Mol. Sci. 2021, 22(3), 1250; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031250 - 27 Jan 2021

Cited by 11 | Viewed by 2510

Abstract

We have previously shown that CD1d-restricted iNKT cells suppress dysregulated IFNγ expression and intestinal inflammation in Yeti mice on the C57BL/6 background. Since type 3 innate lymphoid cells (ILC3s) in mesenteric lymph nodes (MLN) protect against intestinal inflammation in a CD1d-associated manner, we investigated whether crosstalk between iNKT cells and MLN ILC3s controls IFNγ-mediated intestinal inflammation in Yeti mice. We found that Yeti mice display increased levels of ILC3s and that iNKT cell deficiency in Yeti/CD1d KO mice decreases levels of IL22-producing ILC3s during DSS-induced colitis. This finding indicates that iNKT cells and ILC3s cooperate to regulate intestinal inflammation in Yeti mice. Yeti iNKT cells displayed a pronounced anti-inflammatory (IL4- or IL9-producing) phenotype during colitis. Their adoptive transfer to iNKT cell-deficient animals induced a significant increase in IL22 production by ILC3s, indicating that crosstalk between iNKT cells and ILC3s plays a critical role in modulating colitis in Yeti mice. Moreover, we showed that the IL9-producing subset of iNKT cells potently enhances IL22-producing ILC3s in vivo. Taken together, our results identify a central role of the iNKT cell-ILC3 axis in ameliorating IFNγ-mediated intestinal inflammation. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Cytokines in Autoimmune Diseases)

► Show Figures

Figure 1

Review

Jump to: Research

12 pages, 717 KiB

Open AccessReview

Mast Cell Cytokines IL-1, IL-33, and IL-36 Mediate Skin Inflammation in Psoriasis: A Novel Therapeutic Approach with the Anti-Inflammatory Cytokines IL-37, IL-38, and IL-1Ra

by Pio Conti, Fabrizio E. Pregliasco, Rosa G. Bellomo, Carla E. Gallenga, Alessandro Caraffa, Spyros K. Kritas, Dorina Lauritano and Gianpaolo Ronconi

Int. J. Mol. Sci. 2021, 22(15), 8076; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158076 - 28 Jul 2021

Cited by 45 | Viewed by 4466

Abstract

Psoriasis (PS) is a skin disease with autoimmune features mediated by immune cells, which typically presents inflammatory erythematous plaques, and is associated with many comorbidities. PS exhibits excessive keratinocyte proliferation, and a high number of immune cells, including macrophages, neutrophils, Th1 and Th17 lymphocytes, and mast cells (MCs). MCs are of hematopoietic origin, derived from bone marrow cells, which migrate, mature, and reside in vascularized tissues. They can be activated by antigen-provoking overexpression of proinflammatory cytokines, and release a number of mediators including interleukin (IL)-1 and IL-33. IL-1, released by activated keratinocytes and MCs, stimulates skin macrophages to release IL-36—a powerful proinflammatory IL-1 family member. IL-36 mediates both innate and adaptive immunity, including chronic proinflammatory diseases such as psoriasis. Suppression of IL-36 could result in a dramatic improvement in the treatment of psoriasis. IL-36 is inhibited by IL-36Ra, which binds to IL-36 receptor ligands, but suppression can also occur by binding IL-38 to the IL-36 receptor (IL-36R). IL-38 specifically binds only to IL-36R, and inhibits human mononuclear cells stimulated with IL-36 in vitro, sharing the effect with IL-36Ra. Here, we report that inflammation in psoriasis is mediated by IL-1 generated by MCs—a process that activates macrophages to secrete proinflammatory IL-36 inhibited by IL-38. IL-37 belongs to the IL-1 family, and broadly suppresses innate inflammation via IL-1 inhibition. IL-37, in murine models of inflammatory arthritis, causes the suppression of joint inflammation through the inhibition of IL-1. Therefore, it is pertinent to think that IL-37 can play an inhibitory role in inflammatory psoriasis. In this article, we confirm that IL-38 and IL-37 cytokines emerge as inhibitors of inflammation in psoriasis, and hold promise as an innovative therapeutic tool. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Cytokines in Autoimmune Diseases)

► Show Figures

Figure 1

16 pages, 4695 KiB

Open AccessReview

The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics

by Dan-in Jang, A-Hyeon Lee, Hye-Yoon Shin, Hyo-Ryeong Song, Jong-Hwi Park, Tae-Bong Kang, Sang-Ryong Lee and Seung-Hoon Yang

Int. J. Mol. Sci. 2021, 22(5), 2719; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052719 - 08 Mar 2021

Cited by 488 | Viewed by 37875

Abstract

Tumor necrosis factor alpha (TNF-α) was initially recognized as a factor that causes the necrosis of tumors, but it has been recently identified to have additional important functions as a pathological component of autoimmune diseases. TNF-α binds to two different receptors, which initiate signal transduction pathways. These pathways lead to various cellular responses, including cell survival, differentiation, and proliferation. However, the inappropriate or excessive activation of TNF-α signaling is associated with chronic inflammation and can eventually lead to the development of pathological complications such as autoimmune diseases. Understanding of the TNF-α signaling mechanism has been expanded and applied for the treatment of immune diseases, which has resulted in the development of effective therapeutic tools, including TNF-α inhibitors. Currently, clinically approved TNF-α inhibitors have shown noticeable potency in a variety of autoimmune diseases, and novel TNF-α signaling inhibitors are being clinically evaluated. In this review, we briefly introduce the impact of TNF-α signaling on autoimmune diseases and its inhibitors, which are used as therapeutic agents against autoimmune diseases. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Cytokines in Autoimmune Diseases)

► Show Figures

Figure 1

23 pages, 2193 KiB

Open AccessReview

Cytokine Pathways and Investigational Target Therapies in Hidradenitis Suppurativa

by Ester Del Duca, Paola Morelli, Luigi Bennardo, Cosimo Di Raimondo and Steven Paul Nisticò

Int. J. Mol. Sci. 2020, 21(22), 8436; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228436 - 10 Nov 2020

Cited by 32 | Viewed by 5150

Abstract

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease affecting areas with a high density of apocrine glands and characterized by subcutaneous nodules that may evolve into fistulas with pus secretion. Methods: The aim of this review is to investigate all current knowledge on cytokine regulation in the pathogenesis of HS. A systematic literature research using the words “cytokine”, “interleukin”, “pathway”, and “hidradenitis suppurativa” was performed in PubMed/Medline and Scopus/Embase databases. A search of the clinicaltrials.gov website for interventional recruiting and completed trials including the term “hidradenitis suppurativa” was also performed up to August 2020. We will discuss the pathogenetic role of various cytokines in HS and potential therapeutic targets for this debilitating disease. Results: The pathophysiology underlying this complex condition has not been clearly defined. An upregulation of various cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, IL-17, IL-23, and other molecules seems to be related to this inflammatory condition. Various cells, such as lymphocytes T Helper 1 and 17 and keratinocytes seem to be involved in the genesis of this condition. Conclusions: Several future studies and clinical trials are necessary in order to have new knowledge about HS and to properly treat this complex condition. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Cytokines in Autoimmune Diseases)

► Show Figures

Figure 1

14 pages, 279 KiB

Open AccessReview

Blocking IL-17: A Promising Strategy in the Treatment of Systemic Rheumatic Diseases

by Carlos Rafael-Vidal, Nair Pérez, Irene Altabás, Samuel Garcia and Jose M. Pego-Reigosa

Int. J. Mol. Sci. 2020, 21(19), 7100; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197100 - 26 Sep 2020

Cited by 38 | Viewed by 4860

Abstract

Systemic rheumatic diseases are a heterogeneous group of autoimmune disorders that affect the connective tissue, characterized by the involvement of multiple organs, leading to disability, organ failure and premature mortality. Despite the advances in recent years, the therapeutic options for these diseases are still limited and some patients do not respond to the current treatments. Interleukin-17 (IL-17) is a cytokine essential in the defense against extracellular bacteria and fungi. Disruption of IL-17 homeostasis has been associated with the development and progression of rheumatic diseases, and the approval of different biological therapies targeting IL-17 for the treatment of psoriatic arthritis (PsA) and ankylosing spondylitis (AS) has highlighted the key role of this cytokine. IL-17 has been also implicated in the pathogenesis of systemic rheumatic diseases, including systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS) and systemic sclerosis (SSc). The aim of this review is to summarize and discuss the most recent findings about the pathogenic role of IL-17 in systemic rheumatic and its potential use as a therapeutic option. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Cytokines in Autoimmune Diseases)

► Show Figures

Graphical abstract

18 pages, 1035 KiB

Open AccessReview

The Role and Impact of Extracellular Vesicles in the Modulation and Delivery of Cytokines during Autoimmunity

by Mohammed Tayab Hussain, Asif Jilani Iqbal and Lucy Victoria Norling

Int. J. Mol. Sci. 2020, 21(19), 7096; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197096 - 26 Sep 2020

Cited by 18 | Viewed by 3941

Abstract

Cytokines and extracellular vesicles are two methods of initiating and maintaining cellular crosstalk. The role of cytokines in the initiation, progression, and resolution of inflammation has been well studied and more so, their pathophysiological role in the development of autoimmune disease. In recent years, the impact of extracellular vesicles on the progression of autoimmunity has become more widely appreciated. In this review, we discuss the mechanisms that allow extracellular vesicles of various sources to modulate cytokine production, and release, and how extracellular vesicles might be involved in the direct delivery and modulation of cytokine levels. Moreover, we explore what challenges are faced by current therapies and the promising future for extracellular vesicles as therapeutic agents in conditions driven by immune dysregulation. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Cytokines in Autoimmune Diseases)

► Show Figures

Figure 1

12 pages, 291 KiB

Open AccessReview

Interleukin-6 in Rheumatoid Arthritis

by Franco Pandolfi, Laura Franza, Valentina Carusi, Simona Altamura, Gloria Andriollo and Eleonora Nucera

Int. J. Mol. Sci. 2020, 21(15), 5238; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155238 - 23 Jul 2020

Cited by 94 | Viewed by 8301

Abstract

The role of interleukin (IL)-6 in health and disease has been under a lot of scrutiny in recent years, particularly during the recent COVID-19 pandemic. The inflammatory pathways in which IL-6 is involved are also partly responsible of the development and progression of rheumatoid arthritis (RA), opening interesting perspectives in terms of therapy. Anti-IL-6 drugs are being used with variable degrees of success in other diseases and are being tested in RA. Results have been encouraging, particularly when anti-IL-6 has been used with other drugs, such as metothrexate (MTX). In this review we discuss the main immunologic aspects that make anti-IL-6 a good candidate in RA, but despite the main therapeutic options available to target IL-6, no gold standard treatment has been established so far. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Cytokines in Autoimmune Diseases)

13 pages, 1088 KiB

Open AccessReview

Advances in Mast Cell Activation by IL-1 and IL-33 in Sjögren’s Syndrome: Promising Inhibitory Effect of IL-37

by Pio Conti, Luisa Stellin, Alesssandro Caraffa, Carla E. Gallenga, Rhiannon Ross, Spyros K. Kritas, Ilias Frydas, Ali Younes, Paolo Di Emidio and Gianpaolo Ronconi

Int. J. Mol. Sci. 2020, 21(12), 4297; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124297 - 16 Jun 2020

Cited by 17 | Viewed by 4400

Abstract

Sjögren’s syndrome (SS) is a chronic autoimmune inflammatory disease that affects primarily older women and is characterized by irreversible damage of the exocrine glands, including tear (xerophthalmia) and salivary glands (xerostomia). Secretory glands lose their functionality due to the infiltration of immune cells, which produce cytokines and cause inflammation. Primary SS is characterized by dry syndrome with or without systemic commitment in the absence of other pathologies. Secondary SS is accompanied by other autoimmune diseases with high activation of B lymphocytes and the production of autoantibodies, including the rheumatoid factor. Other cells, such as CD4⁺ T cells and mast cells (MCs), participate in SS inflammation. MCs are ubiquitous, but are primarily located close to blood vessels and nerves and can be activated early in autoimmune diseases to express a wide variety of cytokines and chemokines. In the SS acute phase, MCs react by generating chemical mediators of inflammation, tumor necrosis factor (TNF), and other pro-inflammatory cytokines such as interleukin (IL)-1 and IL-33. IL-33 is the specific ligand for ST2 capable of inducing some adaptive immunity TH2 cytokines but also has pro-inflammatory properties. IL-33 causes impressive pathological changes and inflammatory cell infiltration. IL-1 family members can have paracrine and autocrine effects by exacerbating autoimmune inflammation. IL-37 is an IL-1 family cytokine that binds IL-18Rα receptor and/or Toll-like Receptor (TLR)4, exerting an anti-inflammatory action. IL-37 is a natural inhibitor of innate and acquired immunity, and the level is abnormal in patients with autoimmune disorders. After TLR ligand activation, IL-37 mRNA is generated in the cytoplasm, with the production of pro-IL-37 and later mature IL-37 caspase-1 mediated; both precursor and mature IL-37 are biologically active. Here, we discuss, for the first time, the current knowledge of IL-37 in autoimmune disease SS and propose a new therapeutic role. Full article

(This article belongs to the Special Issue Pro-inflammatory and Anti-inflammatory Cytokines in Autoimmune Diseases)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Pro-inflammatory and Anti-inflammatory Cytokines in Autoimmune Diseases

Share This Special Issue

Special Issue Editor

Special Issue Information

Published Papers (10 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI