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.

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.

Mast Cells Mediate Rheumatoid Arthritis-Inhibitory Role of IL-37.

Rheumatoid arthritis (RA) is an autoimmune, chronic inflammatory, disabling arthropathy that severely affects the quality of life. This disease involves several proinflammatory cytokines, including interleukin (IL)-1ß and tumor necrosis factor (TNF). IL-1 induces TNF and vice versa, causing joint damage and cartilage degradation. Current antirheumatic drugs may be effective, but they possess many unwanted side effects. In recent years, inhibitors of proinflammatory cytokines have increasingly entered mainstream clinical practice. Recent evidence indicates that IL-37, which has anti-inflammatory properties, is increased in the serum and is released from white blood cells in patients with RA. Mast cells (MCs), stimulated by the neuropeptide substance P (SP) and IL-33, release IL-1ß and TNF. Recent evidence indicates that large amounts of IL-1ß and TNF can be released from human MCs, which also secrete CXCL8, which promotes migration of immune cells, causing erosion of the bone and cartilage. Treatment with IL-37 can block the MC stimulation and release of inflammatory compounds, attenuating the severity of the disease and/or altering its progression.

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.

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.

Activation of mast cells mediates inflammatory response in psoriasis: Potential new therapeutic approach with IL-37.

Psoriasis (PS) is an autoimmune disorder characterized by chronic inflammatory skin immune-mediated disease which occurs in 2-4% of the worldwide population. PS is associated with an increased risk of cardiovascular disease and depression, and 30% of PS patients are affected with psoriatic arthritis. PS presents excessive keratinocyte proliferation, abnormal differentiation, and elevated mast cell (MC) number. In PS, there are enhanced type I interferon (IFN), angiogenesis, and over-expression of several proinflammatory cytokines, such as tumor necrosis factor and interleukin (IL)-1 family members generated by several immune cells including MCs. MCs are hematopoietic cells that reside in vascularized tissues, which, upon appropriate activation, release proinflammatory cytokines, an effect worsened by acute stress and PS. In recent years, IL-37 emerged as an anti-inflammatory cytokine which binds to alpha chain of the IL-18 receptor alpha (IL-18Rα) and downregulates MyD88. This effect leads to the inhibition of nuclear factor-κB (NF-κB) and mitogen activation protein kinase, with the suppression of inflammatory response. These observations candidate IL-37 as a potential new therapeutic cytokine for inflammatory disorders including PS.

Effect of Factor XIII-A G185T Polymorphism on Visual Prognosis after Photodynamic Therapy for Neovascular Macular Degeneration.

Macular degenerations represent leading causes of central blindness or low vision in developed countries. Most of these severe visual disabilities are due to age-related macular degeneration (AMD) and pathologic myopia (PM), both of which are frequently complicated by subfoveal choroidal neovascularization (CNV). Photodynamic therapy with verteporfin (PDT-V) is still employed for CNV treatment in selected cases or in combined regimen. In Caucasian patients, the common polymorphism G185T of factor XIII-A gene (FXIII-A-G185T; rs5985) has been described as predictor of poor angiographic CNV responsiveness to PDT-V. Nevertheless, the prognostic implications of this pharmacogenetic determinant on long-term visual outcome after a PDT-V regimen have not been evaluated. We retrospectively selected Caucasian patients presenting with treatment-naive CNV and receiving standardized PDT-V protocol for two years. The study population included patients affected by subfoveal CNV secondary to AMD or PM. We assessed the correlations between the polymorphic allele T of FXIII-A-G185T and: (1) total number of photodynamic treatments; and (2) change in visual acuity from baseline to the end of the follow-up period. Considering a total study population of 412 patients with neovascular AMD or PM, the carriers of 185 T-allele of FXIII-A (GT or TT genotype) received a higher number of photodynamic treatments than patients without it (GG wild-type genotype) (p < 0.01; mean number of PDT-V: 5.51 vs. 3.76, respectively). Moreover, patients with 185 T-allele of FXIII-A had a more marked worsening of visual acuity at 24 months than those with the GG-185 wild genotype (p < 0.01; mean difference in logMAR visual acuity: 0.22 vs. 0.08, respectively). The present findings show that the G185T polymorphism of the FXIII-A gene is associated with significant differences in the long-term therapeutic outcomes of patients treated with standardized PDT-V protocol. The comprehensive appraisal of both anti-thrombophilic effects due to FXIII-A G185T variant and photo-thrombotic action of PDT-V toward CNV provides several clues about the rationale of this intriguing pharmacogenetic correlation. Further investigations are warranted to outline the appropriate paradigm for guiding PDT-V utilization in the course of the combined therapeutic protocol for neovascular macular degeneration.

Inflammaging: should this term be suitable for age related macular degeneration too?

INTRODUCTION: Inflammaging is a phenomenon triggered by the conjunction of chronic repetitive and subclinical inflammation from external aggressors and internal inflammatory mechanisms due to the progressive degradation of systems such as the mitochondrial function. Age-related macular degeneration is the leading cause of blindness and visual impairment in patients older than 60 years in developed countries. DISCUSSION: Remarkable correlations have been documented between common or rare immunological/inflammatory gene polymorphisms and AMD, unequivocally indicating the involvement of inflammation and immune-mediated processes (complement activation) in the pathogenesis of this disease. CONCLUSION: Altogether these factors also drive this pathologic condition under the general heading of "Inflammaging".

Retinal phakomatosis and Von Hippel-Lindau peripheral capillary hemangioblastoma: proposal for staged surgery.

PURPOSE: Retinal capillary hemangioblastoma (RCH) is present in about half of the carriers of the VHL (von Hippel-Lindau) gene mutation and can lead to the evolution of blindness. Herewith is a proposal for surgical intraretinal feeder vessel ligature to induce ischemia the phakoma and to resolve the exudative secondary retinal detachment, with satisfying results at the 6 months follow-up end point. METHODS: The patient underwent a chandelier-assisted 23 G pars plana vitrectomy with valved trocars. A bimanual transretinal ligature of the hemangioblastoma's feeder vessel was performed, followed by localized endolaser to ablate the surrounding retina and capillaries, and a Polydimethylsiloxane 1000 (PDMS 1000) final tamponade. After 3 months, exchange PDMS/air/balanced salt solution (BSS), phacoemulsification, and in-the-bag intraocular lens (IOL) implantation were performed. RESULTS: At sixth month, fundus fluorescein angiography (FFA) showed a significant reduction of blood flow in the phakoma. Final best-corrected visual acuity (BCVA) was 6/6 (9 lines gain obtained compared to the baseline time). CONCLUSIONS: This surgical technique seems to be effective and promising for the treatment of VHL retinal capillary hemangioblastomas and their related retinal complications.

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 [...].

Short term effects of extremely low irradiance photobiomodulation on retinal function, in age related macular degeneration.

BACKGROUND: recently much studies evidenced the potential role of photo-biomodulation (PBM) in patients affected by Age-related Macular Degeneration (AMD). We designed a new wearable device for self-medication that employs the same broadband red light described in literature, but with extremely low irradiance. AIM: to demonstrate the safety and effectiveness of low-fluence light stimulations emitted by a LED source with appropriate wavelengths through our new device in improving short-term visual function in patients affected by severe non neovascular AMD. MATERIALS AND METHODS: we prospectively enrolled patients affected by severe non-neovascular AMD with a relative sparing of the foveal region. All the patients were randomly assigned in placebo or in treatment group. The treatment consisted of 10 sessions of 10-min each, using the new device comprised of micro-LEDs that emitted light onto an amorphous support assembled within Metallic eyeglasses. The placebo group blindly underwent the same number of PBM sessions with the micro-LED turned off. Before and after each placebo/treatment sessions all the patients received: optical coherence tomography (OCT), Best-Corrected Visual Acuity (BCVA) and Microperimetry (MP). RESULTS: no significant differences in the anatomical parameters were observed in the two groups. The MP mean sensitivity and the central visual function both far and near significantly improved in the treated group (respectively p < 0.001, p < 0.001). CONCLUSIONS: our pivotal demonstrated that the LED PBM delivered through our new device is a safe and effective tool for improving short-term visual function in patients affected by severe non-neovascular AMD.

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.

Evaluation of Anti-SARS-CoV-2 IgA Response in Tears of Vaccinated COVID-19 Subjects.

Secretory IgA (sIgA), which may play an important role in the early defense against SARS-CoV-2 infection, were detected in the eye of COVID-19 patients. However, an evaluation of the sIgA response in the tears of vaccinated or non-vaccinated COVID-19 subjects is still lacking. Aimed at characterizing sIgA mucosal immunity in the eye, this study analyzed tear samples from 77 COVID-19 patients, including 63 vaccinated and 14 non-vaccinated subjects. The groups showed similar epidemiological features, but as expected, differences were observed in the percentage of asymptomatic/pauci-symptomatic subjects in the vaccinated vs. non-vaccinated cohort (46% and 29% of the total, respectively). Consistent with this, ocular sIgA values, evaluated by a specific quantitative ELISA assay, were remarkably different in vaccinated vs. non-vaccinated group for both frequency (69.8% vs. 57.1%, respectively) and titer (1372.3 U/mL vs. 143.7 U/mL, respectively; p = 0.01), which was significantly differently elevated depending on the type of administered vaccine. The data show for the first time significant differences of available vaccines to elicit sIgA response in the eye and suggest that quantitative tear-based sIgA tests may potentially serve as a rapid and easily accessible biomarker for the assessment of the development of a protective mucosal immunity toward SARS-CoV-2.

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.

Genetic Basis and Molecular Mechanisms of Uveal Melanoma Metastasis: A Focus on Prognosis.

Uveal melanoma (UM) is the most frequently found primary intraocular tumor, although it accounts for only 5% of all melanomas. Despite novel systemic therapies, patient survival has remained poor. Indeed, almost half of UM patients develop metastases from micro-metastases which were undetectable at diagnosis. Genetic analysis is crucial for metastatic risk prediction, as well as for patient management and follow-up. Several prognostic parameters have been explored, including tumor location, basal dimension and thickness, histopathologic cell type, vascular mimicry patterns, and infiltrating lymphocytes. Herein, the Authors review the available literature concerning cytogenetic prognostic markers and biochemical pathways correlated to UM metastasis development.

Advanced Molecular and Immunological Diagnostic Methods to Detect SARS-CoV-2 Infection.

COVID-19 emerged in late 2019 in China and quickly spread across the globe, causing over 521 million cases of infection and 6.26 million deaths to date. After 2 years, numerous advances have been made. First of all, the preventive vaccine, which has been implemented in record time, is effective in more than 95% of cases. Additionally, in the diagnostic field, there are numerous molecular and antigenic diagnostic kits that are equipped with high sensitivity and specificity. Real Time-PCR-based assays for the detection of viral RNA are currently considered the gold-standard method for SARS-CoV-2 diagnosis and can be used efficiently on pooled nasopharyngeal, or oropharyngeal samples for widespread screening. Moreover, additional, and more advanced molecular methods such as droplet-digital PCR (ddPCR), clustered regularly interspaced short palindromic repeats (CRISPR) and next-generation sequencing (NGS), are currently under development to detect the SARS-CoV-2 RNA. However, as the number of subjects infected with SARS-CoV-2 continuously increases globally, health care systems are being placed under increased stress. Thus, the clinical laboratory plays an important role, helping to select especially asymptomatic individuals who are actively carrying the live replicating virus, with fast and non-invasive molecular technologies. Recent diagnostic strategies, other than molecular methods, have been adopted to either detect viral antigens, i.e., antigen-based immunoassays, or human anti-SARS-CoV-2 antibodies, i.e., antibody-based immunoassays, in nasal or oropharyngeal swabs, as well as in blood or saliva samples. However, the role of mucosal sIgAs, which are essential in the control of viruses entering the body through mucosal surfaces, remains to be elucidated, and in particular the role of the immune response in counteracting SARS-CoV-2 infection, primarily at the site(s) of virus entry that appears to be promising.

Virtual learning solutions in COVID-19 era: University Italian Ophthalmology department perspective.

INTRODUCTION: Few months after the COVID-19 pandemic burst, many aspects of the human life, including education, dramatically changed. Because of the lockdown measures taken to limit the virus spread in Italy, in-person teaching and learning have been interrupted in all health care disciplines and readapted in virtual formulae. METHODS: As academic ophthalmology departments, we had to maintain the educational needs of medical and orthoptic students, internships, surgical training of residents, as well as to cover the scientific update of health care personnel (HCPs), and the continuation of research and academic activities. To assure these needs we ideated an educational strategy and a team, which was then translated on a multichannel virtual platform created with Microsoft Teams. RESULTS: In this platform there were 21 channels organized in a public view mode, open to all Team members, or in private view mode to separate non-permanent HCPs, internships, residents, and students' tasks, from permanent HCPs tasks. Virtual channels were dedicated to provide theoretical lessons, clinical cases, surgical video, internal meetings and webinar, to offer news from scientific societies, requests of appointments from biomedical companies, links with ophthalmological websites, to move forward research projects, to participate at institutional academic duties, and to obtain feedbacks from users. Residents continued their training on surgery using a surgical simulator, after consulting an agenda uploaded into the dedicated virtual channel. CONCLUSION: These positive initial results should represent a boost to rapidly proceed with the development of even more versatile virtual learning solutions, given that the forecasts for the duration of the COVID-19 pandemic are not encouraging.

Molecular Mechanisms Related to Oxidative Stress in Retinitis Pigmentosa.

Retinitis pigmentosa (RP) is an inherited retinopathy. Nevertheless, non-genetic biological factors play a central role in its pathogenesis and progression, including inflammation, autophagy and oxidative stress. The retina is particularly affected by oxidative stress due to its high metabolic rate and oxygen consumption as well as photosensitizer molecules inside the photoreceptors being constantly subjected to light/oxidative stress, which induces accumulation of ROS in RPE, caused by damaged photoreceptor's daily recycling. Oxidative DNA damage is a key regulator of microglial activation and photoreceptor degeneration in RP, as well as mutations in endogenous antioxidant pathways involved in DNA repair, oxidative stress protection and activation of antioxidant enzymes (MUTYH, CERKL and GLO1 genes, respectively). Moreover, exposure to oxidative stress alters the expression of micro-RNA (miRNAs) and of long non-codingRNA (lncRNAs), which might be implicated in RP etiopathogenesis and progression, modifying gene expression and cellular response to oxidative stress. The upregulation of the P2X7 receptor (P2X7R) also seems to be involved, causing pro-inflammatory cytokines and ROS release by macrophages and microglia, contributing to neuroinflammatory and neurodegenerative progression in RP. The multiple pathways analysed demonstrate that oxidative microglial activation may trigger the vicious cycle of non-resolved neuroinflammation and degeneration, suggesting that microglia may be a key therapy target of oxidative stress in RP.