About Chlamydia trachomatis. Reply to Garcia-Teillard et al. Trachoma and the Importance of Sexual Infective Route in Developed Countries. Comment on "Gallenga et al. Why the SAFE-S Strategy for Trachoma? Are Musca sorbens or Scatophaga stercoraria Really the Culprit?-A Brief Historical Review from an Italian Point of View. Pathogens 2023, 12, 1419".

The confirmatory comment of Garcia-Teillard et al [...].

Impact of TNF and IL-33 Cytokines on Mast Cells in Neuroinflammation.

Mast cells (MCs) are derived from hematopoietic progenitors, mature in vascularized tissues, and participate in innate and acquired immunity. Neuroinflammation is a highly debated topic in the biomedical literature; however, the impact of tumor necrosis factor (TNF) and IL-33 on MCs in the brain has not been widely addressed. MCs can be activated by IgE binding to FcεRI, as well as by different antigens. After activation, MCs mediate various immunological and inflammatory responses through TNF and IL-33. TNF has two receptors: TNFR1, a p55 molecule, and TNFR2, a p75 molecule. This cytokine is the only one of its kind to be stored in the granules of MCs and can also be generated by de novo synthesis via mRNA. In the central nervous system (CNS), TNF is produced almost exclusively by microglial cells, neurons, astrocytes, and, minimally, by endothelial cells. After its release into brain tissue, TNF rapidly induces the adhesion molecules endothelial leukocyte adhesion molecule 1 (ELAM-1), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) in endothelial cells. TNF causes the chemoattraction of neutrophils by inducing several molecules, including CXC chemokines (IL-8). Both MCs and microglial cells act as a primary barrier against foreign molecules in the CNS, producing pro-inflammatory cytokines such as IL-33. IL-33 belongs to the IL-1 family, is activated through the ST2L/IL1-RAcP receptor complex, and mediates both the innate and adaptive immune response. IL-33 is a nuclear transcription factor expressed in the brain, where it induces pro-inflammatory cytokines (TNF and IL-1) and chemokines (CCL2, CCL3, CCL5, and CXCL10). Therefore, MCs and microglia in the CNS are a source of pro-inflammatory cytokines, including TNF and IL-33, that mediate many brain diseases. The inhibition of TNF and IL-33 may represent a new therapeutic approach that could complement existing neuroinflammatory therapies.

Why the SAFE-S Strategy for Trachoma? Are Musca sorbens or Scatophaga stercoraria Really the Culprit?-A Brief Historical Review from an Italian Point of View.

The biological history of Chlamydia trachomatis is intertwined with the evolution of the man. Infecting Elemental Bodies (EBs), having penetrated mucosal epithelial cells, wrap themselves in a cloak (ĸλαµÎ¹ς) of glycogen that ensures their obligatory intracellular survival and protects this differentiation into Reticulate Bodies (RBs) that feed on cellular ATP. Multiple chemokines and cytokines are involved under the direction of IL-6 in the florid phase and IL-17A in the scar phase. The WHO has successfully identified the SAFE strategy against trachoma (Surgery, Antibiotics, Facial cleansing, Environment) as the blueprint to eliminate the disease by 2020. Recently, interest has been increasingly focused on changing sexual attitudes in different areas of the world, leaving Musca sorbens, Scatophaga stercoraria, and stepsisters fairly blameless, but extolling the role of Chlamydia trachomatis in apparently "sterile" chronic prostatitis or conjunctivitis or, less frequently, in oropharyngitis and proctitis. The addition of an S (SAFE-S) standing for "sexual behavior" was then proposed to also attract the interest and attention not only of Ophthalmologists and Obstetricians/Gynecologists, Urologists/Andrologists, and the School Authorities for information on the prevention of sexually transmitted diseases, but also of Social Physicians and Pediatricians. This means that sexually transmitted infections should be screened in asymptomatic patients with risky sexual behavior or sexual contact with people diagnosed with a transmitted infection.

Macrophage Activation in Follicular Conjunctivitis during the COVID-19 Pandemic.

Among the symptoms of SARS-CoV-2, follicular conjunctivitis has become relevant. The conjunctiva acts as an open lymph node, reacting to the viral antigen that binds the epithelial cells, forming follicles of B cells with activated T cells and NK cells on its surface, which, in turn, talk to monocyte-derived inflammatory infected macrophages. Here, the NLRP3 inflammasome is a major driver in releasing pro-inflammatory factors such as IL-6 and caspase-1, leading to follicular conjunctivitis and bulbar congestion, even as isolated signs in the 'asymptomatic' patient.

Activation of Mast Cells by Neuropeptides: The Role of Pro-Inflammatory and Anti-Inflammatory Cytokines.

Mast cells (MCs) are tissue cells that are derived from bone marrow stem cells that contribute to allergic reactions, inflammatory diseases, innate and adaptive immunity, autoimmunity, and mental disorders. MCs located near the meninges communicate with microglia through the production of mediators such as histamine and tryptase, but also through the secretion of IL-1, IL-6 and TNF, which can create pathological effects in the brain. Preformed chemical mediators of inflammation and tumor necrosis factor (TNF) are rapidly released from the granules of MCs, the only immune cells capable of storing the cytokine TNF, although it can also be produced later through mRNA. The role of MCs in nervous system diseases has been extensively studied and reported in the scientific literature; it is of great clinical interest. However, many of the published articles concern studies on animals (mainly rats or mice) and not on humans. MCs are known to interact with neuropeptides that mediate endothelial cell activation, resulting in central nervous system (CNS) inflammatory disorders. In the brain, MCs interact with neurons causing neuronal excitation with the production of neuropeptides and the release of inflammatory mediators such as cytokines and chemokines. This article explores the current understanding of MC activation by neuropeptide substance P (SP), corticotropin-releasing hormone (CRH), and neurotensin, and the role of pro-inflammatory cytokines, suggesting a therapeutic effect of the anti-inflammatory cytokines IL-37 and IL-38.

Mast Cell Cytokines in Acute and Chronic Gingival Tissue Inflammation: Role of IL-33 and IL-37.

Much evidence suggests autoimmunity in the etiopathogenesis of periodontal disease. In fact, in periodontitis, there is antibody production against collagen, DNA, and IgG, as well as increased IgA expression, T cell dysfunction, high expression of class II MHC molecules on the surface of gingival epithelial cells in inflamed tissues, activation of NK cells, and the generation of antibodies against the azurophil granules of polymorphonuclear leukocytes. In general, direct activation of autoreactive immune cells and production of TNF can activate neutrophils to release pro-inflammatory enzymes with tissue damage in the gingiva. Gingival inflammation and, in the most serious cases, periodontitis, are mainly due to the dysbiosis of the commensal oral microbiota that triggers the immune system. This inflammatory pathological state can affect the periodontal ligament, bone, and the entire gingival tissue. Oral tolerance can be abrogated by some cytokines produced by epithelial cells and activated immune cells, including mast cells (MCs). Periodontal cells and inflammatory-immune cells, including mast cells (MCs), produce cytokines and chemokines, mediating local inflammation of the gingival, along with destruction of the periodontal ligament and alveolar bone. Immune-cell activation and recruitment can be induced by inflammatory cytokines, such as IL-1, TNF, IL-33, and bacterial products, including lipopolysaccharide (LPS). IL-1 and IL-33 are pleiotropic cytokines from members of the IL-1 family, which mediate inflammation of MCs and contribute to many key features of periodontitis and other inflammatory disorders. IL-33 activates several immune cells, including lymphocytes, Th2 cells, and MCs in both innate and acquired immunological diseases. The classic therapies for periodontitis include non-surgical periodontal treatment, surgery, antibiotics, anti-inflammatory drugs, and surgery, which have been only partially effective. Recently, a natural cytokine, IL-37, a member of the IL-1 family and a suppressor of IL-1b, has received considerable attention for the treatment of inflammatory diseases. In this article, we report that IL-37 may be an important and effective therapeutic cytokine that may inhibit periodontal inflammation. The purpose of this paper is to study the relationship between MCs, IL-1, IL-33, and IL-37 inhibition in acute and chronic inflamed gingival tissue.

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.

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.

Powerful anti-inflammatory action of luteolin: Potential increase with IL-38.

Luteolin belongs to the flavone family originally present in some fruits and vegetables, including olives, which decrease intracellular levels of reactive oxygen species (ROS) following the activation of various stimuli. Luteolin inhibits inflammation, a complex process involving immune cells that accumulate at the site of infectious or non-infectious injury, with alteration of the endothelium leading to recruitment of leukocytes. Cytokines have been widely reported to act as immune system mediators, and IL-1 family members evolved to assist in host defense against infections. Interleukin (IL)-1 and Toll-like receptor (TLR) are involved in the innate immunity in almost all living organisms. After being synthesized, IL-1 induces numerous inflammatory mediators including itself, other pro-inflammatory cytokines/chemokines, and arachidonic acid products, which contribute to the pathogenesis of immune diseases. Among the 11 members of the IL-1 family, there are two new cytokines that suppress inflammation, IL-37 and IL-38. IL-38 binds IL-36 receptor (IL-1R6) and inhibits several pro-inflammatory cytokines, including IL-6, through c-Jun N-terminal kinase (JNK) induction and reducing AP1 and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) activity, alleviating inflammatory diseases. Therefore, since luteolin, IL-37 and IL-38 are all anti-inflammatory molecules with different signaling pathways, it is pertinent to recommend the combination of luteolin with these anti-inflammatory cytokines in inflammation.

IL-38 inhibits microglial inflammatory mediators and is decreased in amygdala of children with autism spectrum disorder.

Autism spectrum disorder (ASD) is characterized by impaired social interactions and communication. The pathogenesis of ASD is not known, but it involves activation of microglia. We had shown that the peptide neurotensin (NT) is increased in the serum of children with ASD and stimulates cultured adult human microglia to secrete the proinflammatory molecules IL-1ß and CXCL8. This process is inhibited by the cytokine IL-37. Another cytokine, IL-38, has been reported to have antiinflammatory actions. In this report, we show that pretreatment of cultured adult human microglia with recombinant IL-38 (aa3-152, 1-100 ng/mL) inhibits (P < 0.0001) NT-stimulated (10 nM) secretion of IL-1ß (at 1 ng/mL) and CXCL8 (at 100 ng/mL). In fact, IL-38 (aa3-152, 1 ng/mL) is more potent than IL-37 (100 ng/mL). Here, we report that pretreatment with IL-38 (100 ng/mL) of embryonic microglia (HMC3), in which secretion of IL-1ß was undetectable, inhibits secretion of CXCL8 (P = 0.004). Gene expression of IL-38 and its receptor IL-36R are decreased (P = 0.001 and P = 0.04, respectively) in amygdala from patients with ASD (n = 8) compared to non-ASD controls (n = 8), obtained from the University of Maryland NeuroBioBank. IL-38 is increased (P = 0.03) in the serum of children with ASD. These findings indicate an important role for IL-38 in the inhibition of activation of human microglia, thus supporting its development as a treatment approach for ASD.

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

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.

A new pharmacological approach based on remdesivir aerosolized administration on SARS-CoV-2 pulmonary inflammation: A possible and rational therapeutic application.

The new zoonotic coronavirus (SARS-CoV-2) responsible for coronavirus disease (COVID-19) is a new strain of coronavirus not previously seen in humans and which appears to come from bat species. It originated in Wuhan, Hubei Province, China, and spread rapidly throughout the world, causing over 5,569,679 global cases and 351,866 deaths in almost every country in the world, including Europe, particularly Italy. In general, based on existing data published to date, 80.9% of patients infected with the virus develop mild infection; 13.8% severe pneumonia; 4.7% respiratory failure, septic shock or multi-organ failure; 3% of these cases are fatal. Critical patients have been shown to develop acute respiratory distress syndrome (ARDS) and hospitalization in intensive care units. The average age of patients admitted to hospital is 57-79 years, with one third half with an underlying disease. Asymptomatic infections have also been described, but their frequency is not known. SARS-CoV-2 transmission is mainly airborne from one person to another via droplets. The data available so far seem to indicate that SARS-CoV-2 is capable of producing an excessive immune reaction in the host. The virus attacks type II pneumocytes in the lower bronchi through the binding of the Spike protein (S protein) to viral receptors, of which the angiotensin 2 conversion enzyme (ACE2) receptor is the most important. ACE2 receptor is widely expressed in numerous tissues, including the oropharynx and conjunctiva, but mostly distributed in ciliated bronchial epithelial cells and type II pneumocytes in the lower bronchi. The arrival of SARS-CoV-2 in the lungs causes severe primary interstitial viral pneumonia that can lead to the "cytokine storm syndrome", a deadly uncontrolled systemic inflammatory response triggered by the activation of interleukin 6 (IL-6), whose effect is extensive lung tissue damage and disseminated intravascular coagulation (DIC), that are life-threatening for patients with COVID-19. In the absence of a therapy of proven efficacy, current management consists of off-label or compassionate use therapies based on antivirals, antiparasitic agents in both oral and parenteral formulation, anti-inflammatory drugs, oxygen therapy and heparin support and convalescent plasma. Like most respiratory viruses can function and replicate at low temperatures (i.e. 34-35 °C) and assuming viral thermolability of SARS-CoV-2, local instillation or aerosol of antiviral (i.e. remdesivir) in humid heat vaporization (40°-41 °C) in the first phase of infection (phenotype I, before admission), both in asymptomatic but nasopharyngeal swab positive patients, together with antiseptic-antiviral oral gargles and povidone-iodine eye drops for conjunctiva (0,8-5% conjunctival congestion), would attack the virus directly through the receptors to which it binds, significantly decreasing viral replication, risk of evolution to phenotypes IV and V, reducing hospitalization and therefore death.

Sodium chromo-glycate and palmitoylethanolamide: A possible strategy to treat mast cell-induced lung inflammation in COVID-19.

A novel human coronavirus SARS-CoV-2 (also referred to as CoV-19) that emerged in late 2019 causes Covid-19 disease a respiratory tract infection which provokes about 4 million deaths per year. Unfortunately, to date, there is no specific antiviral treatment for COVID-19. Mast cells (MCs) are immune cells implicated in the pathogenesis of viral infections, where they mediate inflammation. Microbes, including virus, activate MCs through TLR releasing chemical pro-inflammatory compounds and cytokines. Although, in biomedical literature there are only few reports on MCs activation by SARS-CoV-2 infection. The production of pro-inflammatory cytokines by MC viral activation leads to increase pulmonary inflammation and fibrosis. Sodium Chromo-Glycate (SCG) described as a MC stabilizer, prevents the release of inflammatory chemical compounds, improve mouse survival and respiratory pathological changes in lung viral infection and suppresses inflammation. Furthermore, palmitoylethanolamide (PEA) a nuclear factor agonist, an endogenous fatty acid amide, which exerts a variety of biological effects, related to chronic inflammation and pain, is involved also in MCs homeostasis with an inhibitory and protective effect on the respiratory tract during viral infections. Here, we hypothesize for the first time, that SCG and/or PEA suppress MC activation and pro-inflammatory mediators release, playing an anti-inflammatory therapeutic role in the inflamed lung of patients with COVID-19.

New aspect of allergic contact dermatitis, an inflammatory skin disorder mediated by mast cells: Can IL-38 help?

Atopic dermatitis (AD) is an inflammatory reaction of the skin that can occur in several parts of the body and can be provoked or exacerbated by food and/or environmental compounds. Allergic contact dermatitis (ACD) is a potential enhancer of AD, and an epidermal barrier breaker which induces greater penetration of allergens and other compounds. ACD presents an eczematous rash, red and itchy, with inflammation mediated by cytokines. ACD is an immunological disorder caused by contact with an allergic substance (haptens) that involves immunotoxicity, irritation and inflammation. Mast cells (MCs) are important immune cells that intervene, as effector cells, in allergic and anaphylactic reactions, asthma, autoimmune diseases and cancer. In dermatitis, activated MCs release inflammatory chemical mediators and secrete pro-inflammatory cytokines, including interleukin (IL)-1, TNF, and IL-33. In addition, IL-1 activates MCs to generate a number of cytokines and chemokines, which aggravate inflammation. IL-38 cytokine, an IL-1 family member, is secreted by activated immune cells, including macrophages and lymphocytes, and possesses anti-inflammatory activity. IL-38, by binding IL-36 receptor (IL-36R), provokes suppression of inflammation in many immune diseases. In particular, IL-38 inhibits the generation of IL-1, IL-6 and IL-8 along with other cytokines/chemokines. Here, we hypothesize for the first time that IL-38 may suppresses the inflammatory response in dermatitis, exerting beneficial therapeutic effect.

Microglia and mast cells generate proinflammatory cytokines in the brain and worsen inflammatory state: Suppressor effect of IL-37.

Brain microglia cells are responsible for recognizing foreign bodies and act by activating other immune cells. Microglia react against infectious agents that cross the blood-brain barrier and release pro-inflammatory cytokines including interleukin (IL)-1ß, IL-33 and tumor necrosis factor (TNF). Mast cells (MCs) are immune cells also found in the brain meninges, in the perivascular spaces where they create a protective barrier and release pro-inflammatory compounds, such as IL-1ß, IL-33 and TNF. IL-1ß binds to the IL-1R1 receptor and activates a cascade of events that leads to the production of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activation of the immune system. IL-33 is a member of the IL-1 family expressed by several immune cells including microglia and MCs and is involved in innate and adaptive immunity. IL-33 is a pleiotropic cytokine which binds the receptor ST2 derived from TLR/IL-1R super family and is released after cellular damage (also called "alarmin"). These cytokines are responsible for a number of brain inflammatory disorders. Activated IL-1ß in the brain stimulates microglia, MCs, and perivascular endothelial cells, mediating various inflammatory brain diseases. IL-37 also belongs to the IL-1 family and has the capacity to suppress IL-1ß with an anti-inflammatory property. IL-37 deficiency could activate and enhance myeloid differentiation (MyD88) and p38-dependent protein-activated mitogenic kinase (MAPK) with an increase in IL-1ß and IL-33 exacerbating neurological pathologies. In this article we report for the first time that microglia communicate and collaborate with MCs to produce pro-inflammatory cytokines that can be suppressed by IL-37 having a therapeutic potentiality.

The Epithelial-to-Mesenchymal Transition as a Possible Therapeutic Target in Fibrotic Disorders.

Fibrosis is a chronic and progressive disorder characterized by excessive deposition of extracellular matrix, which leads to scarring and loss of function of the affected organ or tissue. Indeed, the fibrotic process affects a variety of organs and tissues, with specific molecular background. However, two common hallmarks are shared: the crucial role of the transforming growth factor-beta (TGF-ß) and the involvement of the inflammation process, that is essential for initiating the fibrotic degeneration. TGF-ß in particular but also other cytokines regulate the most common molecular mechanism at the basis of fibrosis, the Epithelial-to-Mesenchymal Transition (EMT). EMT has been extensively studied, but not yet fully explored as a possible therapeutic target for fibrosis. A deeper understanding of the crosstalk between fibrosis and EMT may represent an opportunity for the development of a broadly effective anti-fibrotic therapy. Here we report the evidences of the relationship between EMT and multi-organ fibrosis, and the possible therapeutic approaches that may be developed by exploiting this relationship.

Impact of mast cells in fibromyalgia and low-grade chronic inflammation: Can IL-37 play a role?

Fibromyalgia (FM) is a disease characterized by chronic widespread pain, fatigue, aches, joint stiffness, depression, cognitive dysfunction, and nonrestorative sleep. In FM, neurotransmission and glial activation can occur with an increase in inflammatory cytokines and involvement of mast cells (MCs) in the skin. FM skin biopsies show an increase in the number of MCs, as well as the production of corticotropin releasing hormone and substance P (SP) by the neurons, which in turn activate MCs to release neurosensitizing proinflammatory substances, such as cytokines, secreted preformed mediators, and lipids, which can exacerbate low-grade inflammation. In fact, certain proinflammatory cytokines are higher in FM and mediate muscle pain, the mechanism of which is not yet clear. MC-derived tumor necrosis factor (TNF) induces nerve growth factor (NGF) and participates in nerve fiber elongation in skin hypersensitivity. IL-37 is an inhibitor of proinflammatory IL-1 family members, which are generated and released by MCs. The goal of this article is to demonstrate that inflammatory cytokines and MC products play a role in FM and that inflammation may be inhibited by IL-37. Here, we propose IL-37 as a cytokine that contributes to improve the pathogenesis of FM by blocking IL-1 family members.

IL-37 is increased in brains of children with autism spectrum disorder and inhibits human microglia stimulated by neurotensin.

Autism spectrum disorder (ASD) does not have a distinct pathogenesis or effective treatment. Increasing evidence supports the presence of immune dysfunction and inflammation in the brains of children with ASD. In this report, we present data that gene expression of the antiinflammatory cytokine IL-37, as well as of the proinflammatory cytokines IL-18 and TNF, is increased in the amygdala and dorsolateral prefrontal cortex of children with ASD as compared to non-ASD controls. Gene expression of IL-18R, which is a receptor for both IL-18 and IL-37, is also increased in the same brain areas of children with ASD. Interestingly, gene expression of the NTR3/sortilin receptor is reduced in the amygdala and dorsolateral prefrontal cortex. Pretreatment of cultured human microglia from normal adult brains with human recombinant IL-37 (1 to 100 ng/mL) inhibits neurotensin (NT)-stimulated secretion and gene expression of IL-1ß and CXCL8. Another key finding is that NT, as well as the proinflammatory cytokines IL-1ß and TNF increase IL-37 gene expression in cultured human microglia. The data presented here highlight the connection between inflammation and ASD, supporting the development of IL-37 as a potential therapeutic agent of ASD.

Mast Cells May Regulate The Anti-Inflammatory Activity of IL-37.

Mast cells are unique immune cells involved in allergic reactions, but also in immunity and inflammation. Interleukin 37 (IL-37) has emerged as an important regulatory cytokine with ability to inhibit immune and inflammatory processes. IL-37 is made primarily by macrophages upon activation of toll-like receptors (TLR) leading to generation of mature IL-37 via the action of caspase 1. In this review, we advance the premise that mast cells could regulate the anti-inflammatory activity of the IL-37 via their secretion of heparin and tryptase. Extracellular IL-37 could either dimerize in the presence of heparin and lose biological activity, or be acted upon by proteases that can generate even more biologically active IL-37 forms. Molecules that could selectively inhibit the secretion of mast cell mediators may, therefore, be used together with IL-37 as novel therapeutic agents.

New insight into systemic mastocytosis mediated by cytokines IL-1ß and IL-33: Potential inhibitory effect of IL-37.

Systemic mastocytosis in various forms is characterized by mast cell (MC) infiltration of the bone marrow and other internal organs. The most common form is the indolent one with life expectancy similar to the normal population, while the systemic aggressive myeloproliferative type presents serious damage to various organs and is associated with mature and immature atypical mast cells. In systemic mastocytosis patients, MCs could be activated with consequent severe anaphylactic reactions, along with other symptoms. MCs, which are reactive to a variety of external factors such as allergens or other inflammatory or physical stimuli, derive from pluripotent cellular progenitor CD34+ which leaves the bone marrow as CD34+/CD17+ for implantation in the tissues where they reach maturation. MCs participate in the innate and adaptive immune system where they play a role in host defense. Activation of MCs occurs through the binding of IgE to FcεRI receptor, and initiates the phosphorylation and activation of the p38 tyrosine MAP kinase. After various reactions there is a subsequent translation and generation of pro-inflammatory cytokines which are strongly linked to allergic inflammation and mastocytosis. Human cytokine interleukin-37 (IL-37), a unique IL-1ß family member, has strong protective and anti-inflammatory properties, influencing cellular metabolism. We investigated the effect of IL-37 on inflammation in mastocytosis and report that the hematopoietic expression of IL-37 can reduce the inflammatory state in this disease. IL-37 limits excessive inflammation, which suggests that IL-37 may be beneficial to the metabolic and inflammatory process and is a candidate as a potential new therapeutic agent.