Mast Cells and Interleukins

Haque T.T., Frischmeyer-Guerrerio P.A.

Mast cells (MC) are a key effector cell in multiple types of immune responses, including atopic conditions. Allergic diseases have been steadily rising across the globe, creating a growing public health problem. IgE-mediated activation of MCs leads to the release of potent mediators that can have dire clinical consequences. Current therapeutic options to inhibit MC activation and degranulation are limited; thus, a better understanding of the mechanisms that regulate MC effector functions in allergic inflammation are necessary in order to develop effective treatment options with minimal side effects. Several cytokines have been identified that play multifaceted roles in regulating MC activation, including TGFβ, IL-10, and IL-33, and others that appear to serve primarily anti-inflammatory functions, including IL-35 and IL-37. Here, we review the literature examining cytokines that regulate MC-mediated allergic immune responses.

Atiakshin D., Kostin A., Buchwalow I., Samoilova V., Tiemann M.

Mast cells (MCs) produce a variety of mediators, including proteases—tryptase, chymase, and carboxypeptidases—which are important for the immune response. However, a detailed assessment of the mechanisms of biogenesis and excretion of proteases in melanoma has yet to be carried out. In this study, we present data on phenotype and secretory pathways of proteases in MCs in the course of melanoma. The development of melanoma was found to be accompanied by the appearance in the tumor-associated MC population of several pools with a predominant content of one or two specific proteases with a low content or complete absence of others. Elucidation of the molecular and morphological features of the expression of MC proteases in melanoma allows us a fresh perspective of the pathogenesis of the disease, and can be used to clarify MCs classification, the disease prognosis, and evaluate the effectiveness of ongoing antitumor therapy.

Conti P., Pregliasco F.E., Bellomo R.G., Gallenga C.E., Caraffa A., Kritas S.K., Lauritano D., Ronconi G.

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.

Briukhovetska D., Dörr J., Endres S., Libby P., Dinarello C.A., Kobold S.

Interleukins and associated cytokines serve as the means of communication for innate and adaptive immune cells as well as non-immune cells and tissues. Thus, interleukins have a critical role in cancer development, progression and control. Interleukins can nurture an environment enabling and favouring cancer growth while simultaneously being essential for a productive tumour-directed immune response. These properties of interleukins can be exploited to improve immunotherapies to promote effectiveness as well as to limit side effects. This Review aims to unravel some of these complex interactions. This Review provides an update of interleukins in tumour biology, covering the milestones of the latest discoveries of interleukin-related mechanisms in cancer, together with their application in clinical practice. It includes an overview of current clinical trials and breakthrough preclinical concepts.

Nagata K., Nishiyama C.

Mast cells (MCs) play critical roles in Th2 immune responses, including the defense against parasitic infections and the initiation of type I allergic reactions. In addition, MCs are involved in several immune-related responses, including those in bacterial infections, autoimmune diseases, inflammatory bowel diseases, cancers, allograft rejections, and lifestyle diseases. Whereas antigen-specific IgE is a well-known activator of MCs, which express FcεRI on the cell surface, other receptors for cytokines, growth factors, pathogen-associated molecular patterns, and damage-associated molecular patterns also function as triggers of MC stimulation, resulting in the release of chemical mediators, eicosanoids, and various cytokines. In this review, we focus on the role of interleukin (IL)-10, an anti-inflammatory cytokine, in MC-mediated immune responses, in which MCs play roles not only as initiators of the immune response but also as suppressors of excessive inflammation. IL-10 exhibits diverse effects on the proliferation, differentiation, survival, and activation of MCs in vivo and in vitro. Furthermore, IL-10 derived from MCs exerts beneficial and detrimental effects on the maintenance of tissue homeostasis and in several immune-related diseases including contact hypersensitivity, auto-immune diseases, and infections. This review introduces the effects of IL-10 on various events in MCs, and the roles of MCs in IL-10-related immune responses and as a source of IL-10.

Javadrashid D., Baghbanzadeh A., Derakhshani A., Leone P., Silvestris N., Racanelli V., Solimando A.G., Baradaran B.

Genetic alterations, especially the K-Ras mutation, carry the heaviest burden in the progression of pancreatic precursor lesions into pancreatic ductal adenocarcinoma (PDAC). The tumor microenvironment is one of the challenges that hinder the therapeutic approaches from functioning sufficiently and leads to the immune evasion of pancreatic malignant cells. Mastering the mechanisms of these two hallmarks of PDAC can help us in dealing with the obstacles in the way of treatment. In this review, we have analyzed the signaling pathways involved in PDAC development and the immune system’s role in pancreatic cancer and immune checkpoint inhibition as next-generation therapeutic strategy. The direct targeting of the involved signaling molecules and the immune checkpoint molecules, along with a combination with conventional therapies, have reached the most promising results in pancreatic cancer treatment.

Harrison T.W., Chanez P., Menzella F., Canonica G.W., Louis R., Cosio B.G., Lugogo N.L., Mohan A., Burden A., McDermott L., Garcia Gil E., Zangrilli J.G., Pohl W., Voves R., Deschampheleire M., et. al.

Summary Background ANDHI was done to assess the efficacy of benralizumab, including onset of effect and impact on health-related quality of life (HRQOL), exacerbation rate, lung function, and nasal polyposis symptoms. Methods This phase 3b, randomised, double-blind, parallel-group, placebo-controlled ANDHI study was completed in adults (aged 18–75 years) with severe eosinophilic asthma with at least 2 exacerbations in the previous year, despite high-dose inhaled corticosteroid plus additional controllers, screening blood eosinophil counts of at least 150 cells per μL, and an Asthma Control Questionnaire 6 (ACQ-6) score of 1·5 or more. Patients who met eligibility criteria were randomly assigned (2:1; stratified by previous exacerbation count [two, or three or more], maintenance oral corticosteroid use, and region), using an integrated web-based response system, to receive benralizumab at 30 mg every 8 weeks (first three doses given 4 weeks apart) or matched placebo for 24 weeks. Primary efficacy measure was annualised asthma exacerbation rate, with rate ratio (RR) calculated over the approximate 24-week follow-up. Secondary efficacy measures included change from baseline to end of treatment (week 24) in St George's Respiratory Questionnaire (SGRQ) total score (key secondary endpoint), FEV1, peak expiratory flow (PEF), ACQ-6, Predominant Symptom and Impairment Assessment (PSIA), Clinician Global Impression of Change (CGI-C), Patient Global Impression of Change (PGI-C), and Sino-Nasal Outcome Test-22 (SNOT-22). All efficacy analyses, except for SNOT-22, were summarised and analysed using the full analysis set on an intention-to-treat population (all randomly assigned patients receiving investigational product, regardless of protocol adherence or continued participation in the study). SNOT-22 was summarised for the subgroup of patients with physician-diagnosed nasal polyposis with informed consent. This study is registered with ClinicalTrials.gov, NCT03170271. Findings Between July 7, 2017, and Sept 25, 2019, 656 patients received benralizumab (n=427) or placebo (n=229). Baseline characteristics were consistent with severe eosinophilic asthma. Benralizumab significantly reduced exacerbation risk by 49% compared with placebo (RR estimate 0·51, 95% CI 0·39–0·65; p 5%) were nasopharyngitis (30 [7%]), headache (37 [9%]), sinusitis (28 [7%]), bronchitis (22 [5%]), and pyrexia (26 [6%]). Fewer serious adverse events were reported for benralizumab (23 [5%]) versus placebo (25 [11%]), and the only common serious adverse event (experienced by >1% of patients) was worsening of asthma, which was reported for nine (2%) patients in the benralizumab group and nine (4%) patients in the placebo group. Interpretation Our results extend the efficacy profile of benralizumab for patients with severe eosinophilic asthma, showing early clinical benefits in patient-reported outcomes, HRQOL, lung function, and nasal polyposis symptoms. Funding AstraZeneca.

Valent P., Akin C., Hartmann K., Nilsson G., Reiter A., Hermine O., Sotlar K., Sperr W.R., Escribano L., George T.I., Kluin-Nelemans H.C., Ustun C., Triggiani M., Brockow K., Gotlib J., et. al.

The origin and functions of mast cells (MCs) have been debated since their description by Paul Ehrlich in 1879. MCs have long been considered 'reactive bystanders' and 'amplifiers' in inflammatory processes, allergic reactions, and host responses to infectious diseases. However, knowledge about the origin, phenotypes and functions of MCs has increased substantially over the past 50 years. MCs are now known to be derived from multipotent hematopoietic progenitors, which, through a process of differentiation and maturation, form a unique hematopoietic lineage residing in multiple organs. In particular, MCs are distinguishable from basophils and other hematopoietic cells by their unique phenotype, origin(s), and spectrum of functions, both in innate and adaptive immune responses and in other settings. The concept of a unique MC lineage is further supported by the development of a distinct group of neoplasms, collectively referred to as mastocytosis, in which MC precursors expand as clonal cells. The clinical consequences of the expansion and/or activation of MCs are best established in mastocytosis and in allergic inflammation. However, MCs have also been implicated as important participants in a number of additional pathologic conditions and physiological processes. In this article, we review concepts regarding MC development, factors controlling MC expansion and activation, and some of the fundamental roles MCs may play in both health and disease. We also discuss new concepts for suppressing MC expansion and/or activation using molecularly-targeted drugs.

Eissmann M.F., Buchert M., Ernst M.

The Interleukin (IL-)1 family IL33 is best known for eliciting type 2 immune responses by stimulating mast cells (MCs), regulatory T-cells (Tregs), innate lymphoid cells (ILCs) and other immune cells. MCs and IL33 provide critical control of immunological and epithelial homeostasis in the gastro-intestinal (GI) tract. Meanwhile, the role of MCs in solid malignancies appears tissue-specific with both pro and anti-tumorigenic activities. Likewise, IL33 signaling significantly shapes immune responses in the tumor microenvironment, but these effects remain often dichotomous when assessed in experimental models of cancer. Thus, the balance between tumor suppressing and tumor promoting activities of IL33 are highly context dependent, and most likely dictated by the mixture of cell types responding to IL33. Adding to this complexity is the promiscuous nature by which MCs respond to cytokines other than IL33 and release chemotactic factors that recruit immune cells into the tumor microenvironment. In this review, we integrate the outcomes of recent studies on the role of MCs and IL33 in cancer with our own observations in the GI tract. We propose a working model where the most abundant IL33 responsive immune cell type is likely to dictate an overall tumor-supporting or tumor suppressing outcome in vivo. We discuss how these opposing responses affect the therapeutic potential of targeting MC and IL33, and highlight the caveats and challenges facing our ability to effectively harness MCs and IL33 biology for anti-cancer immunotherapy.

Mitamura Y., Nunomura S., Furue M., Izuhara K.

Interleukin (IL)-24 is a member of the IL-20 family of cytokines and is produced by various types of cells, such as CD4 + T cells, NK cells, mast cells, keratinocytes, bronchial epithelial cells, and myofibroblasts. Previous studies suggest that IL-24 plays an essential role in the pathogenesis of pro-inflammatory autoimmune disorders such as psoriasis, arthritis, and inflammatory bowel diseases. However, the role of IL-24 in the pathogenesis of allergic diseases has been elusive. It has already been reported that IL-24 is involved in the pathogenesis of allergic lung and skin diseases. Moreover, we have recently revealed for the first time the pivotal functions of IL-24 in IL-13–mediated skin barrier dysfunction in atopic dermatitis (AD), which is known to be a characteristic of AD caused by Th2 cytokines such as IL-4 or IL-13. In this review, we show recent advances in the basic characteristics of IL-24 and its novel functions in the pathogenesis of allergic skin inflammation, focusing on AD. A better understanding of the role of IL-24 in allergic diseases can lead to the development of new therapeutic options.

Sabag D.A., Matanes L., Bejar J., Sheffer H., Barzilai A., Church M.K., Toubi E., Maurer M., Vadasz Z.

Background Chronic spontaneous urticaria (CSU) is considered an autoimmune disorder in 50% of cases at least, in which T- and mast cell mediators are considered to be the primary cause of symptoms. However, H1 -antihistamines, cyclosporine A, and omalizumab fail to achieve complete symptom amelioration in up to 70% of patients. This suggests that other inflammatory pathways are involved and that additional and more effective treatments need to be developed. Objective This preliminary report examines the possibility that interleukin-17 (IL-17), a cytokine involved in the pathogenesis of many autoimmune diseases, may contribute to CSU and its inhibition may offer a relevant therapeutic target. Methods The expression of IL-17A in skin biopsies of 20 CSU patients and 10 healthy controls was determined by quantitative histomorphometry. We also assessed the response to secukinumab (anti-IL-17A) treatment patients of eight severe CSU (7-day urticaria activity score UAS7 32-40) who were H1 -antihistamine and omalizumab-resistant. Results Increased numbers of CD4+ T cells and mast cells were present in both lesional and non-lesional skin of CSU patients compared with healthy controls. Both types of cells were strongly positive for IL-17A and found to be in close proximity to each other. All eight patients treated with the anti-IL-17A antibody, secukinumab, showed significant improvement in CSU disease activity. The action of secukinumab was shown to be relatively slow in onset. The significant reduction in disease activity from baseline UAS7 was demonstrated to be 55% and 82% at 30 and 90 days, respectively. Conclusions These findings suggest that IL-17 is involved in the pathogenesis of CSU and that IL-17 should be investigated as a therapeutic target in future studies with larger numbers of patients.

Conti P., Stellin L., Caraffa A., Gallenga C.E., Ross R., Kritas S.K., Frydas I., Younes A., Di Emidio P., Ronconi G.

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.

Li W., Ding F., Zhai Y., Tao W., Bi J., Fan H., Yin N., Wang Z.

Allergic contact dermatitis (ACD), characterized predominantly by erythema, vesiculation, and pruritus, is a T cell-mediated skin inflammatory condition. Among immune cells involved in ACD, mast cells (MCs) play an essential role in its pathogenesis. As an inhibitor of proinflammatory IL-1 family members, interleukin 37 (IL-37) has been shown to ameliorate inflammatory responses in various allergic diseases. In this study, we assessed the immunomodulatory effect of IL-37 on allergic inflammation using a 2,4-dinitrofluorobenzene (DNFB)-induced ACD rat model and isolated rat peritoneal mast cells (RPMCs). Systematic application of IL-37 significantly relieved ear swelling, reduced inflammatory cell infiltration, decreased inflammatory cytokine production (TNF-α, IL-1β, IFN-γ, and IL-13), inhibited MC recruitment, lowered IgE levels, and reduced IL-33 production in the local ear tissues with DNFB challenge. Additionally, RPMCs isolated from ACD rats with IL-37 intervention showed downregulation of IL-6, TNF-α, IL-13, and MCP-1 production following IL-33 stimulation, and reduction of β-hexosaminidase and histamine release under DNP-IgE/HSA treatment. Moreover, IL-37 treatment also significantly restrained NF-κB activation and P38 phosphorylation in ACD RPMCs. SIS3, a specific Smad3 inhibitor, abolished the suppressive effects of IL-37 on MC-mediated allergic inflammation, suggesting the participation of Smad3 in the anti-ACD effect of IL-37. These findings indicated that IL-37 protects against IL-33-regulated MC inflammatory responses via inhibition of NF-κB and P38 MAPK activation accompanying the regulation of Smad3 in rats with ACD.

Komi D.E., Mortaz E., Amani S., Tiotiu A., Folkerts G., Adcock I.M.

Mast cells (MCs) are granular cells of the innate immune system which develop from CD34+/CD117+ progenitors and play a role in orchestrating adaptive immune responses. They have a well-known role in allergic reactions following immunoglobulin (Ig)E-mediated activation of the cell-surface expressed IgE high-affinity receptor (FcεRI). MCs can also respond to various other stimuli due to the expression of a variety of receptors including toll-like receptors (TLRs), immunoglobulin (IgG) receptors (FcγR), complement receptors such as C5a (CD88) expressed by skin MCs, neuropeptides receptors including nerve growth factor receptor, (NGFR), cytokines receptors such as (IL)-1R and IL-3R, and chemokines receptors including CCR-1 and CCR-3. MCs release three groups of mediators upon degranulation differentiated according to their chemical composition, storage, and time to release. These include preformed mediators (mainly histamine, tryptase, and chymase), de novo synthesized mediators such as prostaglandin (PG)D2, leukotriene (LT)B4 and LTD4, and cytokines including IL-1β, IL-3, tumor necrosis factor (TNF)α, and transforming growth factor(TGF)-β. Emerging evidence indicates a role for IgE-independent MC activation in the late-stage asthmatic response as well as in non-allergic airway diseases including chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and lung cancer. MC infiltration/activation has been reported in some, but not all, studies of lung cancer. MC-derived TNF-α possesses tumor-suppressive activity while IL-1β supports tumor progression and metastasis. In IPF lungs, an increase in density of tryptase- and chymase-positive MCs (MCTC) and overexpression of TGF-β support the fibrosis progression. MC-derived chymase activates latent TGF-β that induces the differentiation of fibroblasts to matrix-producing myofibroblasts. In summary, increasing evidence highlights a critical role of MCs in non-allergic diseases that may indicate new approaches for therapy.

Ragipoglu D., Dudeck A., Haffner-Luntzer M., Voss M., Kroner J., Ignatius A., Fischer V.

Mast cells (MCs) are important sensor and effector cells of the immune system that are involved in many physiological and pathological conditions. Increasing evidence suggests that they also play an important role in bone metabolism and bone disorders. MCs are located in the bone marrow and secrete a wide spectrum of mediators, which can be rapidly released upon activation. Many of these mediators can exert osteocatabolic effects by promoting osteoclast formation (e.g. histamine, tumor necrosis factor (TNF), interleukin-6 (IL-6)) and/or by inhibiting osteoblast activity (e.g. IL-1, TNF). By contrast, MCs could potentially act in an osteoprotective manner by stimulating osteoblasts (e.g. transforming growth factor-β) or reducing osteoclastogenesis (e.g. IL-12, interferon-γ). Experimental studies investigating MC functions in physiological bone turnover using MC-deficient mouse lines give contradictory results, reporting delayed or increased bone turnover or no influence depending on the mouse model used. By contrast, the involvement of MCs in various pathological conditions affecting bone is evident. MCs may contribute to the pathogenesis of primary and secondary osteoporosis as well as inflammatory disorders, including rheumatoid arthritis and osteoarthritis, because increased numbers of MCs were found in patients suffering from these diseases. The clinical observations could be largely confirmed in experimental studies using MC-deficient mouse models, which also provide mechanistic insights. MCs also regulate bone healing after fracture by influencing the inflammatory response towards the fracture, vascularization, bone formation, and callus remodeling by osteoclasts. This review summarizes the current view and understanding of the role of MCs on bone in both physiological and pathological conditions.

Ribatti D.

Shu F., Yu J., Liu Y., Wang F., Gou G., Wen M., Luo C., Lu X., Hu Y., Du Q., Xu J., Xie R.

Abstract Mast cells (MCs) are critical components of both innate and adaptive immune processes. They play a significant role in protecting human health and in the pathophysiology of various illnesses, including allergies, cardiovascular diseases and autoimmune diseases. Recent studies in tumor-related research have demonstrated that mast cells exert a substantial influence on tumor cell behavior and the tumor microenvironment, exhibiting both pro- and anti-tumor effects. Specifically, mast cells not only secrete mediators related to pro-tumor function such as trypsin-like enzymes, chymotrypsin, vascular endothelial cell growth factor and histamine, but also mediators related to anti-tumor progression such as cystatin C and IL-17F. This dual role of mast cells renders them an under-recognized but very promising target for tumor immunotherapy. Digestive system tumors, characterized by high morbidity and associated mortality rates globally, are increasingly recognized as a significant healthcare burden. This paper examines the influence of mast cell-derived mediators on the development of tumors in the digestive system. It also explores the prognostic significance of mast cells in patients with various gastrointestinal cancers at different stages of the disease. Additionally, the article investigates the interactions between mast cells and immune cells, as well as the potential relationships among intratumoral bacteria, immune cells, and mast cell within digestive system microenvironment. The aim is to propose new strategies for the immunotherapy of digestive system tumors by targeting mast cells.

Somma F., Romano B., Maresca D.C., Maisto M., Tenore G., Ianaro A., Ercolano G.

Trybus E., Trybus W.

Despite significant progress in the field of clinical oncology in terms of diagnostic and treatment methods, the results of anticancer therapy are still not fully satisfactory, especially due to limited response and high toxicity. This has forced the need for further research to finding alternative ways to improve success rates in oncological treatment. A good solution to this problem in the context of rapidly obtaining an effective drug that works on multiple levels of cancer and is also safe is the global strategy of repurposing an existing drug. Research into other applications of an existing drug enables a precise assessment of its possible mechanisms of action and, consequently, the broadening of therapeutic indications. This strategy is also supported by the fact that most non-oncological drugs have pleiotropic effects, and most of the diseases for which they were originally intended are multifactorial, which in turn is a very desirable phenomenon due to the heterogeneous and multifaceted biology of cancer. In this review, we will mainly focus on the anticancer potential of H1 antihistamines, especially the new generation that were not originally intended for cancer therapy, to highlight the relevant signaling pathways and discuss the properties of these agents for their judicious use based on the characteristic features of cancer.

Sadek A., Khramtsova Y., Yushkov B.

The formation of mature spermatozoa originates from spermatogonial stem cells (SSCs) located near the basement membrane of the seminiferous tubules. This developmental process, known as spermatogenesis, is tightly regulated to ensure continuous sperm production. A critical aspect of this regulation is the balance between SSC differentiation and self-renewal, which is directed by various factors guiding SSCs in either of these two directions. The SSC niche, defined functionally rather than anatomically, includes all factors necessary for SSC maintenance. These factors are produced by cells surrounding the SSC niche, collectively creating the microenvironment of the seminiferous tubules. Coordination between the cells in this microenvironment is essential for the proper function of the SSC niche and successful spermatogenesis. Testicular mast cells (MCs) significantly influence the regulation of this niche, as they contain various biologically active substances that regulate a wide range of physiological processes and contribute to different pathological conditions affecting fertility. This review explores the effects of testicular MCs on SSCs, their role in regulating spermatogenesis under normal and pathological conditions, and their interactions with other components of the testicular microenvironment, with a focus on their potentially critical impact on spermatogenesis and male fertility.

Yang Y., Sun J., You H., Sun Y., Song Y., Shen Z., Liu T., Guan D., Zhou Y., Cheng S., Wang C., Yu G., Zhu C., Tang Z.

Urushiol-induced allergic contact dermatitis (ACD) is a chronic inflammatory skin disease in which skin barrier dysfunction leads to pruritus and eczematous lesions. ACD is triggered by immune imbalance. Aloe emodin is an anthraquinone derivative extracted from rhubarb, aloe and other traditional Chinese medicines. It has a wide range of pharmacological effects, including anti-inflammatory, anti-tumor, and anti-allergic effects. The purpose of our study was to demonstrate the effectiveness of aloe-emodin on urushiol-induced acute pruritus and allergic contact dermatitis. The results showed that urushiol could stimulate keratinocytes to release chemokines CXCL1, CXCL2, CCL2, TSLP, and TNF-α, which recruit or activate mast cells. Aloe-emodin treatment inhibited inflammatory-response-induced mast cell degranulation in skin lesions and suppressed the expression of inflammatory cytokines, such as interleukin-4, and interleukin-6. Therefore, the results indicate that aloe-emodin can improve urushiol-induced acute pruritus and allergic contact dermatitis in mice by inhibiting mast cell degranulation.

Haggag N.Z., El-Shinnawy N.A., Badr G., Yousef H.N., Abd-Elhalem S.S.

Abstract Background The relationship between the alarming cytokine interleukin-33 (IL-33) and lung autophagy in systemic anaphylaxis mouse models is not yet fully elucidated, hence, the current study attempts to explain the regulation of lung autophagy in systemic anaphylactic mouse models. IL-33 plays a critical role in endoplasmic reticulum (ER) stress and autophagy regulation via insulin-like growth factor-binding protein-3 (IGFBP-3). Results The results of the present study confirmed the induction of systemic anaphylaxis in mice through the elevated mast cell mediators in the peritoneal lavage. Consequently, lung stress triggered IL-33 secretion that influenced autophagy markers; IGFBP-3, activating transcription factor-6 (ATF-6), autophagy related gene 4B (ATG4B), p62, microtubule-associated protein light chain3-II (LC3-II) as well as DNA damage-regulated autophagy modulator 1 (DRAM1). Conclusion This research is a trial to investigate lung autophagy in compound 48/80 or ovalbumin-induced systemic anaphylaxis mouse models and pay a particular attention to the role of IL-33 in lung autophagy in such models. Graphical abstract

Januskevicius A., Vasyle E., Rimkunas A., Malakauskas K.

Asthma is a chronic inflammatory process that leads to airway narrowing, causing breath loss followed by spasms, wheezing, and shortness of breath. Within the asthmatic lungs, interaction among various immune cells and structural cells plays a significant role in orchestrating an inflammatory response in which eosinophils hold central importance. In these settings, allergens or other environmental exposures commonly drive the immune response to recruit eosinophils to the airways. The appearance of eosinophils in the airways indicates a dynamic interplay of various cell types within lung tissue and does not represent a passive effect of inflammation. The cellular cross-talk causes the persistence of eosinophilic inflammation, and if left untreated, it results in long-term damage to the airway structure and function. Further exacerbation of the condition occurs because of this. We discuss how this complex interplay of eosinophils, immune, and structural cells within the airway microenvironment leads to the distinct pathophysiological features in asthma, the variability in disease severity, and the response to biological treatments.

Ed Nignpense B., Budiono B., Francis N., Blanchard C., Santhakumar A.B.

Gohal G., Moni S.S., Bakkari M.A., Elmobark M.E.

Asthma, a complex disease characterized by persistent airway inflammation, remains an urgent global health concern. We explored the critical role of allergic biomarkers and dysregulated immune system in asthma through an extensive literature review in databases such as Web of Science, PubMed, EMBASE, Scopus, and Google Scholar. This review summarizes the growing data on the pivotal role of allergic biomarkers and dysregulated immune system in the development and evolution of asthma. Recent studies have uncovered several biomarkers that elucidate intrinsic allergic mechanisms in individuals with asthma. This article highlights these biomarkers’ potential in predicting asthma onset, assessing its intensity, guiding therapeutic interventions, and tracking disease progression. We also explore the innovative therapeutic prospects arising from the convergence of allergy and dysregulated immune system in asthma and emphasize the potential for precision medicine approaches. Understanding allergic biomarkers intertwined with a dysregulated immune system heralds a new era in asthma treatment and points to improved and individualized treatment modalities.

Sergi D., Melloni M., Passaro A., Neri L.M.

Breast cancer (BC) represents the most prevalent cancer in women at any age after puberty. From a pathogenetic prospective, despite a wide array of risk factors being identified thus far, poor metabolic health is emerging as a putative risk factor for BC. In particular, type 2 diabetes mellitus (T2DM) provides a perfect example bridging the gap between poor metabolic health and BC risk. Indeed, T2DM is preceded by a status of hyperinsulinemia and is characterised by hyperglycaemia, with both factors representing potential contributors to BC onset and progression. Additionally, the aberrant secretome of the dysfunctional, hypertrophic adipocytes, typical of obesity, characterised by pro-inflammatory mediators, is a shared pathogenetic factor between T2DM and BC. In this review, we provide an overview on the effects of hyperglycaemia and hyperinsulinemia, hallmarks of type 2 diabetes mellitus, on breast cancer risk, progression, treatment and prognosis. Furthermore, we dissect the role of the adipose-tissue-secreted adipokines as additional players in the pathogenesis of BC. Finally, we focus on microalgae as a novel superfood and a source of nutraceuticals able to mitigate BC risk by improving metabolic health and targeting cellular pathways, which are disrupted in the context of T2DM and obesity.

Mahmood A.S., Al-Bassam W.W.

Eczema is a common skin disease associated with inflammation. Interleukin (IL)-24 is crucial in the pathogenesis of inflammatory diseases like eczema. The study objective was the assessment of IL-24 serum levels and its gene polymorphisms in eczematic Iraqi patients. This retrospective case-control study involved 145 participants, divided into 82 patients with eczema and 63 healthy controls. An enzyme-linked immunosorbent assay measured serum IL-24, while polymerase chain reaction and Sanger DNA sequencing were used for genotype analysis. Serum IL-24 level was significantly higher (P value < .001) in patients compared to controls (41.6 [interquartile range (IQR): 28.9–53.6] vs 9.8 [IQR: 0.8–19.6] pg/mL, respectively). DNA sequence illustrated 2 SNPs with polymorphic frequencies (rs1150256 G/A and rs3093425 del/ins). The first SNP (rs1150256 G/A) showed 3 genotypes (GG, AA, and G/A), while the second SNP (rs3093425) showed 3 genotypes (-/G del/Ins, G Ins/Ins, and - del/del). The subsequent investigation revealed the presence of the following findings within the DNA sequence of the PCR amplified region (329bp). In the control group, all participants had GG/G (wild type) genotype/allele for the rs1150256 SNP, while in eczematic patients, 24.4% GG, 50% GA, and 25.6% AA. For the second SNP genotype (rs3093425 del/ins), the genotype frequencies in patients vs control were (24.4% vs 84.1%, 50.0% vs 11.1%, and 25.6% vs 4.8; Del/Del, Del/Ins, and Ins/Ins, respectively). The presence of Ins compared to Del increased the risk of eczema by 8.91 (4.66–17.03); OR (95% CI). In conclusion, IL-24 is a good predictor of eczema and A-allele carrier for rs1150256 SNP, and insertion-allele carrier for rs3093425 SNP is associated with elevated serum IL-24 and higher risk of eczema.

Oh J., Yoon H., Joo J., Im W., Chun S.

Ginseng leaves are known to contain high concentrations of bioactive compounds, such as ginsenosides, and have potential as a treatment for various conditions, including fungal infections, cancer, obesity, oxidative stress, and age-related diseases. This study assessed the impact of ginseng leaf extract (GLE) on mast cell-mediated allergic inflammation and atopic dermatitis (AD) in DNCB-treated mice. GLE reduced skin thickness and lymph node nodules and suppressed the expression and secretion of histamine and pro-inflammatory cytokines. It also significantly lowered the production of inflammatory response mediators including ROS, leukotriene C4 (LTC4), prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS). GLE inhibited the phosphorylation of MAPKs (ERK, P38, JNK) and the activation of NF-κB, which are both linked to inflammatory cytokine expression. We demonstrated that GLE’s inhibitory effect on mast cell-mediated allergic inflammation is due to the blockade of the NF-κB and inflammasome pathways. Our findings suggest that GLE can be an effective therapeutic agent for mast-cell mediated and allergic inflammatory conditions.

Hehar N.K., Chigbu D.I.

Vernal keratoconjunctivitis (VKC) is a complex and multifactorial disease process that employs Th2 cell-mediated immunologic processes, which involves the overexpression of interleukin 4 (IL-4), IL-5, IL-9, IL-13, and IL-31, and the activation of mast cells that release IL-5 and CCL-11, recruiting eosinophils to the site of inflammation. The disease primarily affects young males and is more common in regions with warm climates. VKC is characterized by persistent and recurrent conjunctival inflammation that can adversely affect the patient’s quality of life, and, when inadequately treated, may lead to a host of ocular complications, such as corneal shield ulcers and scarring. The major distinct forms of VKC include limbal or palpebral, which may occur in combination. The clinicopathological features of VKC include the presence of pseudogerontoxon, limbal gelatinous hyperplasia, and perilimbal hyperpigmentation. Topical immunomodulators are effective anti-steroidal options for controlling severe and chronic cases of VKC. This review will provide a brief overview of topical immunomodulators, including cyclosporin and tacrolimus, and will highlight the clinical manifestations, pathological mechanisms, and fibroproliferative changes in the conjunctiva that can result from recurrent disease.

Chigbu D.I., Karbach N.J., Abu S.L., Hehar N.K.

Allergic conjunctivitis is one of the common immune hypersensitivity disorders that affect the ocular system. The clinical manifestations of this condition exhibit variability contingent upon environmental factors, seasonal dynamics, and genetic predisposition. While our comprehension of the pathophysiological engagement of immune and nonimmune cells in the conjunctiva has progressed, the same cannot be asserted for the cytokines mediating this inflammatory cascade. In this review, we proffer a comprehensive description of interleukins 4 (IL-4), IL-5, IL-6, IL-9, IL-13, IL-25, IL-31, and IL-33, as well as thymic stromal lymphopoietin (TSLP), elucidating their pathophysiological roles in mediating the allergic immune responses on the ocular surface. Delving into the nuanced functions of these cytokines holds promise for the exploration of innovative therapeutic modalities aimed at managing allergic conjunctivitis.