Emerging Therapeutic Potential of Polyphenols from Geranium sanguineum L. in Viral Infections, Including SARS-CoV-2.

The existing literature supports the anti-inflammatory, antioxidant, and antiviral capacities of the polyphenol extracts derived from Geranium sanguineum L. These extracts exhibit potential in hindering viral replication by inhibiting enzymes like DNA polymerase and reverse transcriptase. The antiviral properties of G. sanguineum L. seem to complement its immunomodulatory effects, contributing to infection resolution. While preclinical studies on G. sanguineum L. suggest its potential effectiveness against COVID-19, there is still a lack of clinical evidence. Therefore, the polyphenols extracted from this herb warrant further investigation as a potential alternative for preventing and treating COVID-19 infections.

Evaluation of Cell-Specific Alterations in Alzheimer's Disease and Relevance of In Vitro Models.

Alzheimer's disease (AD) is a neurodegenerative disorder classically characterized by two neuropathological hallmarks: ß-amyloid plaques and tau tangles in the brain. However, the cellular and molecular mechanisms involved in AD are still elusive, which dampens the possibility of finding new and more effective therapeutic interventions. Current in vitro models are limited in modelling the complexity of AD pathogenesis. In this study, we aimed to characterize the AD expression signature upon a meta-analysis of multiple human datasets, including different cell populations from various brain regions, and compare cell-specific alterations in AD patients and in vitro models to highlight the appropriateness and the limitations of the currently available models in recapitulating AD pathology. The meta-analysis showed consistent enrichment of the Rho GTPases signaling pathway among different cell populations and in the models. The accuracy of in vitro models was higher for neurons and lowest for astrocytes. Our study underscores the particularly low fidelity in modelling down-regulated genes across all cell populations. The top enriched pathways arising from meta-analysis of human data differ from the enriched pathways arising from the overlap. We hope that our data will prove useful in indicating a starting point in the development of future, more complex, 3D in vitro models.

The newly engineered monoclonal antibody ON104, targeting the oxidized Macrophage Migration Inhibitory Factor (oxMIF), ameliorates clinical and histopathological signs of collagen-induced arthritis.

Macrophage Migration Inhibitory Factor (MIF) is a pleiotropic inflammatory cytokine that emerged as a pivotal regulator in the pathogenesis of several autoimmune diseases including rheumatoid arthritis (RA). MIF occurs in two immunologically distinct conformational isoforms, indicated as reduced (redMIF) and oxidized MIF (oxMIF) where the latter exerts disease-related activities. In this study we demonstrate the presence of circulating oxMIF in RA patients and investigate the in vivo effects of an oxMIF-neutralizing antibody in a murine model of RA. By advanced antibody engineering we generated the fully human anti-oxMIF antibody ON104 with abolished effector functions. The therapeutic potential of ON104 was tested in a model of Collagen-Induced Arthritis (CIA) in DBA/1j mice. At disease onset, the mice received ON104 twice a week for three weeks. Clinical symptoms were assessed daily, and histological examinations of the joints were performed at the end of the study. Antibody ON104, specifically targeting human and murine oxMIF, is highly affine and does not elicit effector functions in vitro. The treatment of CIA mice with ON104 profoundly modulated disease progression with marked amelioration of clinical signs of arthritis that was associated with reduced synovial and cartilage damage and reduced F4/80-positive macrophages in the joints. These data prove that oxMIF is a relevant target in a well-known model of human RA and its specific neutralization by the antibody ON104 ameliorates clinical and histological signs of the disease in the so-treated mice. Thus, ON104 represents a new and promising treatment option for RA and possibly other autoimmune diseases.

Evaluation of the Involvement of Heme Oxygenase-1 Expression in Discoid Lupus Erythematosus Lesions.

Discoid lupus erythematosus (DLE) is a chronic autoimmune disease that primarily affects the skin, causing red, scaly patches that may be disfiguring and can cause permanent scarring. This study aimed to investigate the potential clinical and therapeutic applications of heme oxygenase-1 (HMOX1) in the context of DLE. Immunohistochemical staining and bioinformatics analysis were performed on skin biopsy samples from DLE patients to examine the levels of HMOX1 and to correlate with markers of inflammation. Our study revealed a negative correlation between HMOX1 levels and the inflammatory status of DLE lesions, as well as an inverse correlation between HMOX1 levels and the infiltration of M1 macrophages and activated mastocytes. These findings suggest that HMOX1 plays a crucial role in the regulation of inflammation in DLE and could be a potential therapeutic target and biomarker for DLE.

Transcriptional upregulation of galectin-3 in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune, demyelinating disorder of the central nervous system (CNS) affecting approximately 2.5 million people worldwide. The mechanisms underlying the pathogenesis of MS are still only partially elucidated. Galectins are a family of ß-galactoside-binding lectins that are involved in the regulation of immune and inflammatory responses and have been shown to exert a role in the maintenance of central nervous system (CNS) homeostasis. There has been an increasing interest in the role of galectin-3 in neuroinflammation and neurodegeneration. In the current study, we have evaluated the expression levels of galectin-3 in different cellular populations involved in the etiopathogenesis of MS. We have observed dramatically higher transcriptomic levels of galectin-3 in encephalitogenic CD4+ T cells in a preclinical model of MS, the MOG-induced experimental allergic encephalomyelitis (EAE). Also, significantly higher levels of galectin-3 were found in microglial cells, astrocytes, and oligodendrocytes isolated from the spinal cord of EAE mice, as well as in human MS-related white matter lesions. Modular co-expression analysis revealed that galectin-3 is co-expressed with genes involved in the regulation of microglia, cytokine production, and chemotaxis. This is the first comprehensive analysis of the expression of galectin-3 in MS, further strengthening its potential pathogenetic role in the etiopathogenesis of this CNS autoimmune disorder.

Anti-COVID-19 Potential of Ellagic Acid and Polyphenols of Punica granatum L.

Pomegranate (Punica granatum L.) is a rich source of polyphenols, including ellagitannins and ellagic acid. The plant is used in traditional medicine, and its purified components can provide anti-inflammatory and antioxidant activity and support of host defenses during viral infection and recovery from disease. Current data show that pomegranate polyphenol extract and its ellagitannin components and metabolites exert their beneficial effects by controlling immune cell infiltration, regulating the cytokine secretion and reactive oxygen and nitrogen species production, and by modulating the activity of the NFκB pathway. In vitro, pomegranate extracts and ellagitannins interact with and inhibit the infectivity of a range of viruses, including SARS-CoV-2. In silico docking studies show that ellagitannins bind to several SARS-CoV-2 and human proteins, including a number of proteases. This warrants further exploration of polyphenol-viral and polyphenol-host interactions in in vitro and in vivo studies. Pomegranate extracts, ellagitannins and ellagic acid are promising agents to target the SARS-CoV-2 virus and to restrict the host inflammatory response to viral infections, as well as to supplement the depleted host antioxidant levels during the stage of recovery from COVID-19.

Preventive and Therapeutic Effects of Punica granatum L. Polyphenols in Neurological Conditions.

Pomegranate (Punica granatum L.) is a polyphenol-rich food and medicinal plant containing flavonols, anthocyanins, and tannins. Ellagitannins (ETs) are the most abundant polyphenols in pomegranate. A growing body of research shows that polyphenol-rich pomegranate extracts and their metabolites target multiple types of brain cell and support their redox balance, proliferation and survival, as well as cell signaling. Independent studies have demonstrated that the significant neuroprotective effects of ETs are mediated by their antioxidant and anti-inflammatory effects, their chelating properties, by their ability to activate various signaling pathways, as well as the ability to influence mitochondrial damage, thus regulating autophagy, apoptosis and neurotransmitter signaling. The multitude of in vitro and in vivo studies summarized in the present review suggest that pomegranate polyphenols act on both neuronal and glial cells directly, and also affect blood-brain barrier function, restoring redox balance in the blood and brain and increasing blood flow to the brain.

Past, Present and (Foreseeable) Future of Biological Anti-TNF Alpha Therapy.

Due to the key role of tumor necrosis factor-alpha (TNF-α) in the pathogenesis of immunoinflammatory diseases, TNF-α inhibitors have been successfully developed and used in the clinical treatment of autoimmune disorders. Currently, five anti-TNF-α drugs have been approved: infliximab, adalimumab, golimumab, certolizumab pegol and etanercept. Anti-TNF-α biosimilars are also available for clinical use. Here, we will review the historical development as well as the present and potential future applications of anti-TNF-α therapies, which have led to major improvements for patients with several autoimmune diseases, such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PS) and chronic endogenous uveitis. Other therapeutic areas are under evaluation, including viral infections, e.g., COVID-19, as well as chronic neuropsychiatric disorders and certain forms of cancer. The search for biomarkers able to predict responsiveness to anti-TNF-α drugs is also discussed.

Gene Co-Expression Network Modular Analysis Reveals Altered Immune Mechanisms in HIV-HAND.

Although the introduction of HAART has completely changed the natural course of HIV infection, the number of chronic forms of HIV-associated neurocognitive disorder (HAND) has risen. It is estimated that up to half of subjects undergoing HAART therapy exhibit mild cognitive impairments. In the current study, we apply the gene co-expression network modular analysis, a well-established system biology approach, to the gene expression profiles of cases from the National NeuroAIDS Tissue Consortium (NNTC). We observed a negative enrichment for genes associated with the control of immune responses and putatively regulated by the transcription factors IRF8 and SPI1 and by both type I and II interferons. Our study provides evidence of altered immune responses, which are likely associated with the occurrence of HAND in the absence of HIV encephalitis (HIVE).

Computational Analysis of Pathogenetic Pathways in Alzheimer's Disease and Prediction of Potential Therapeutic Drugs.

BACKGROUND: Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease which affects more than 50 million patients and represents 60-80% of all cases of dementia. Mutations in the APP gene, mostly affecting the γ-secretase site of cleavage and presenilin mutations, have been identified in inherited forms of AD. METHODS: In the present study, we performed a meta-analysis of the transcriptional signatures that characterize two familial AD mutations (APPV7171F and PSEN1M146V) in order to characterize the common altered biomolecular pathways affected by these mutations. Next, an anti-signature perturbation analysis was performed using the AD meta-signature and the drug meta-signatures obtained from the L1000 database, using cosine similarity as distance metrics. RESULTS: Overall, the meta-analysis identified 1479 differentially expressed genes (DEGs), 684 downregulated genes, and 795 upregulated genes. Additionally, we found 14 drugs with a significant anti-similarity to the AD signature, with the top five drugs being naftifine, moricizine, ketoconazole, perindopril, and fexofenadine. CONCLUSIONS: This study aimed to integrate the transcriptional profiles associated with common familial AD mutations in neurons in order to characterize the pathogenetic mechanisms involved in AD and to find more effective drugs for AD.

Characterization of Altered Molecular Pathways in the Entorhinal Cortex of Alzheimer's Disease Patients and In Silico Prediction of Potential Repurposable Drugs.

Alzheimer's disease (AD) is the most common cause of dementia worldwide and is characterized by a progressive decline in cognitive functions. Accumulation of amyloid-ß plaques and neurofibrillary tangles are a typical feature of AD neuropathological changes. The entorhinal cortex (EC) is the first brain area associated with pathologic changes in AD, even preceding atrophy of the hippocampus. In the current study, we have performed a meta-analysis of publicly available expression data sets of the entorhinal cortex (EC) in order to identify potential pathways underlying AD pathology. The meta-analysis identified 1915 differentially expressed genes (DEGs) between the EC from normal and AD patients. Among the downregulated DEGs, we found a significant enrichment of biological processes pertaining to the "neuronal system" (R-HSA-112316) and the "synaptic signaling" (GO:0099536), while the "regulation of protein catabolic process" (GO:00042176) and "transport of small molecules" (R-HSA-382551) resulted in enrichment among both the upregulated and downregulated DEGs. Finally, by means of an in silico pharmacology approach, we have prioritized drugs and molecules potentially able to revert the transcriptional changes associated with AD pathology. The drugs with a mostly anti-correlated signature were: efavirenz, an anti-retroviral drug; tacrolimus, a calcineurin inhibitor; and sirolimus, an mTOR inhibitor. Among the predicted drugs, those potentially able to cross the blood-brain barrier have also been identified. Overall, our study found a disease-specific set of dysfunctional biological pathways characterizing the EC in AD patients and identified a set of drugs that could in the future be exploited as potential therapeutic strategies. The approach used in the current study has some limitations, as it does not account for possible post-transcriptional events regulating the cellular phenotype, and also, much clinical information about the samples included in the meta-analysis was not available. However, despite these limitations, our study sets the basis for future investigations on the pathogenetic processes occurring in AD and proposes the repurposing of currently used drugs for the treatment of AD patients.

Oral Delivery of Encapsulated All-Trans Retinoic Acid Ameliorates Disease in Rodent Models of Colitis.

BACKGROUND: All-trans retinoic acid (ATRA) is a biologically active isomer of retinoic acid (RA). Topical ATRA (retin-a, retin-a micro, atralin, renova, and avita) is the active pharmaceutical ingredient for FDA-approved treatments for acne and skin wrinkles. Oral formulations (Vesanoid) treat acute promyelocytic leukemia, but oral dosing can induce severe side effects. Despite benefits in various rodent models of inflammatory bowel disease (IBD), toxicity and controversial clinical observations have diminished enthusiasm for ATRA IBD clinical trials. To circumvent these issues and to use ATRA's key role in maintaining gut tolerance, we developed a poly(lactic-co-glycolic acid) (PLGA) microsphere (MS) encapsulated ATRA formulation aimed at directing ATRA delivery to immune structures of the gut, limiting systemic exposure. Initially, ATRA MS was developed as a component of a combinatorial product (TreXTAM) that also contained encapsulated transforming growth factor (TGF)-ß and ATRA in a 1:2 w/w ratio. Although the combination was optimal, benefit was also observed when ATRA MS was given alone in the CD4+ CD25-T-cell adoptive transfer (ACT) colitis model. METHODS: We used the ACT and DSS-induced murine models of colitis to expand on the dose-dependent effects of oral ATRA MS when given alone. The DSS model was also used to compare the efficacy of ATRA MS and soluble ATRA, while healthy animals were used to compare the pharmacokinetics of the two drugs. RESULTS: In both the ACT and DSS-induced murine models of colitis, ATRA MS was observed to be effective in ameliorating disease. ATRA MS was also observed to be more effective than soluble ATRA in these models and displayed more favorable pharmacokinetics. CONCLUSIONS: We suggest ATRA MS, as a standalone product, may attenuate IBD and perhaps limit fibrosis, while limiting systemic side effects.

A review: Antibody-dependent enhancement in COVID-19: The not so friendly side of antibodies.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents an unprecedented global public health emergency with economic and social consequences. One of the main concerns in the development of vaccines is the antibody-dependent enhancement phenomenon, better known as ADE. In this review, we provide an overview of SARS-CoV-2 infection as well as the immune response generated by the host. On the bases of this principle, we also describe what is known about the ADE phenomenon in various viral infections and its possible role as a limiting factor in the development of new vaccines and therapeutic strategies.

Therapeutic Potential of Alpha-Lipoic Acid in Viral Infections, including COVID-19.

Oxidative stress (OS), resulting from a disrupted balance between reactive oxygen species (ROS) and protective antioxidants, is thought to play an important pathogenetic role in several diseases, including viral infections. Alpha-lipoic acid (LA) is one of the most-studied and used natural compounds, as it is endowed with a well-defined antioxidant and immunomodulatory profile. Owing to these properties, LA has been tested in several chronic immunoinflammatory conditions, such as diabetic neuropathy and metabolic syndrome. In addition, a pharmacological antiviral profile of LA is emerging, that has attracted attention on the possible use of this compound for the cotreatment of several viral infections. Here, we will review the emerging literature on the potential use of LA in viral infections, including COVID-19.

Transcriptomic Data Analysis Reveals a Down-Expression of Galectin-8 in Schizophrenia Hippocampus.

Schizophrenia (SCZ) is a severe psychiatric disorder with several clinical manifestations that include cognitive dysfunction, decline in motivation, and psychosis. Current standards of care treatment with antipsychotic agents are often ineffective in controlling the disease, as only one-third of SCZ patients respond to medications. The mechanisms underlying the pathogenesis of SCZ remain elusive. It is believed that inflammatory processes may play a role as contributing factors to the etiology of SCZ. Galectins are a family of ß-galactoside-binding lectins that contribute to the regulation of immune and inflammatory responses, and previous reports have shown their role in the maintenance of central nervous system (CNS) homeostasis and neuroinflammation. In the current study, we evaluated the expression levels of the galectin gene family in post-mortem samples of the hippocampus, associative striatum, and dorsolateral prefrontal cortex from SCZ patients. We found a significant downregulation of LGALS8 (Galectin-8) in the hippocampus of SCZ patients as compared to otherwise healthy donors. Interestingly, the reduction of LGALS8 was disease-specific, as no modulation was observed in the hippocampus from bipolar nor major depressive disorder (MDD) patients. Prediction analysis identified TBL1XR1, BRF2, and TAF7 as potential transcription factors controlling LGALS8 expression. In addition, MIR3681HG and MIR4296 were negatively correlated with LGALS8 expression, suggesting a role for epigenetics in the regulation of LGALS8 levels. On the other hand, no differences in the methylation levels of LGALS8 were observed between SCZ and matched control hippocampus. Finally, ontology analysis of the genes negatively correlated with LGALS8 expression identified an enrichment of the NGF-stimulated transcription pathway and of the oligodendrocyte differentiation pathway. Our study identified LGALS8 as a disease-specific gene, characterizing SCZ patients, that may in the future be exploited as a potential therapeutic target.

Altered Expression of TSPAN32 during B Cell Activation and Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease with various clinical features. Autoreactive B cells play a role in disease pathogenesis, through the production of multiple autoantibodies, which form immune complexes and induce the inflammatory response and tissue damage associated with SLE. Recently, tetraspanins, and in particular, TSPAN32, have been recognized to play a central role in immunity, as they are involved in various biological processes, such as the antigen presentation and the activation of lymphocytes. Evidence suggests that tetraspanins could represent in the future a target for therapeutic purposes in patients suffering from autoimmune/immunoinflammatory disorders. In the present study, by performing in silico analyses of high-throughput data, we evaluated the expression levels of TSPAN32 in B cell activation and investigated its modulation in circulating B cells from SLE patients. Our data show that B cell activation is associated with a significant downregulation of TSPAN32. Additionally, significantly lower levels of TSPAN32 were observed in circulating plasmablasts from SLE patients as compared to healthy donor plasmablasts. In addition, type I interferons (IFNs)-related genes were enriched among the genes negatively correlated to TSPAN32, in SLE plasmablasts. Accordingly, IFN-α is able to induce a dose-dependent downregulation of TSPAN32 in B cells. Overall, the data here presented suggest the potential use of TSPAN32 as a diagnostic marker and therapeutic target for the evaluation and management of humoral immune responses in chronic diseases, such as SLE.

Antimicrobial properties of Lactobacillus cell-free supernatants against multidrug-resistant urogenital pathogens.

The healthy vaginal microbiota is dominated by Lactobacillus spp., which provide an important critical line of defense against pathogens, as well as giving beneficial effects to the host. We characterized L. gasseri 1A-TV, L. fermentum 18A-TV, and L. crispatus 35A-TV, from the vaginal microbiota of healthy premenopausal women, for their potential probiotic activities. The antimicrobial effects of the 3 strains and their combination against clinical urogenital bacteria were evaluated together with the activities of their metabolites produced by cell-free supernatants (CFSs). Their beneficial properties in terms of ability to interfere with vaginal pathogens (co-aggregation, adhesion to HeLa cells, biofilm formation) and antimicrobial activity mediated by CFSs were assessed against multidrug urogenital pathogens (S. agalactiae, E. coli, KPC-producing K. pneumoniae, S. aureus, E. faecium VRE, E. faecalis, P. aeruginosa, P. mirabilis, P. vulgaris, C. albicans, C. glabrata). The Lactobacilli tested exhibited an extraordinary ability to interfere and co-aggregate with urogenital pathogens, except for Candida spp., as well as to adhere to HeLa cells and to produce biofilm in the Lactobacillus combination. Lactobacillus CFSs and their combination revealed a strong bactericidal effect on the multidrug resistant indicator strains tested, except for E. faecium and E. faecalis. The antimicrobial activity was maintained after heat treatment but decreased after enzymatic treatment. All Lactobacilli showed lactic dehydrogenase activity and production of D- and L-lactic acid isomers on Lactobacillus CFSs, while only 1A-TV and 35A-TV released hydrogen peroxide and carried helveticin J and acidocin A bacteriocins. These results suggest that they can be employed as a new vaginal probiotic formulation and bio-therapeutic preparation against urogenital infections. Further, in vivo studies are needed to evaluate human health benefits in clinical situations.

A Network Medicine Approach for Drug Repurposing in Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive hereditary muscular disease caused by a lack of dystrophin, leading to membrane instability, cell damage, and inflammatory response. However, gene-editing alone is not enough to restore the healthy phenotype and additional treatments are required. In the present study, we have first conducted a meta-analysis of three microarray datasets, GSE38417, GSE3307, and GSE6011, to identify the differentially expressed genes (DEGs) between healthy donors and DMD patients. We have then integrated this analysis with the knowledge obtained from DisGeNET and DIAMOnD, a well-known algorithm for drug-gene association discoveries in the human interactome. The data obtained allowed us to identify novel possible target genes and were used to predict potential therapeutical options that could reverse the pathological condition.

Potential Mucosal Irritation Discrimination of Surface Disinfectants Employed against SARS-CoV-2 by Limacus flavus Slug Mucosal Irritation Assay.

Preventive measures have proven to be the most effective strategy to counteract the spread of the SARS-CoV-2 virus. Among these, disinfection is strongly suggested by international health organizations' official guidelines. As a consequence, the increase of disinfectants handling is going to expose people to the risk of eyes, mouth, nose, and mucous membranes accidental irritation. To assess mucosal irritation, previous studies employed the snail Arion lusitanicus as the mucosal model in Slug Mucosal Irritation (SMI) assay. The obtained results confirmed snails as a suitable experimental model for their anatomical characteristics superimposable to the human mucosae and the different easily observed readouts. Another terrestrial gastropod, Limacus flavus, also known as " Yellow slug ", due to its larger size and greater longevity, has already been proposed as an SMI assay alternative model. In this study, for the first time, in addition to the standard parameters recorded in the SMI test, the production of yellow pigment in response to irritants, unique to the snail L. flavus, was evaluated. Our results showed that this species would be a promising model for mucosal irritation studies. The study conducted testing among all those chemical solutions most commonly recommended against the SARS-CoV-2 virus.

Macrophage Migration Inhibitory Factor (MIF) and Its Homologue d-Dopachrome Tautomerase (DDT) Inversely Correlate with Inflammation in Discoid Lupus Erythematosus.

Discoid Lupus Erythematosus (DLE) is a chronic cutaneous disease of unknown etiology and of immunoinflammatory origin that is characterized by inflammatory plaques and may lead to disfiguring scarring and skin atrophy. Current treatments are limited, with a large proportion of patients either poorly or not responsive, which makes DLE an unmet medical need. Macrophage migration inhibitory factor (MIF) is the prototype of a pleiotropic family of cytokine that also includes the recently discovered homologue D-dopachrome tautomerase (DDT) or MIF2. MIF and DDT/MIF-2 exert several biological properties, primarily, but not exclusively of a proinflammatory nature. MIF and DDT have been suggested to play a key role in the pathogenesis of several autoimmune diseases, such as multiple sclerosis and type 1 diabetes, as well as in the development and progression of certain forms of cancers. In the present study, we have performed an immunohistochemistry analysis for the evaluation of MIF in DLE lesions and normal skin. We found high levels of MIF in the basal layer of the epidermis as well as in the cutaneous appendage (eccrine glands and sebocytes) of normal skin. In DLE lesions, we observed a significant negative correlation between the expression of MIF and the severity of inflammation. In addition, we performed an analysis of MIF and DDT expression levels in the skin of DLE patients in a publicly available microarray dataset. Interestingly, while these in silico data only evidenced a trend toward reduced levels of MIF, they demonstrated a significant pattern of expression and correlation of DDT with inflammatory infiltrates in DLE skins. Overall, our data support a protective role for endogenous MIF and possibly DDT in the regulation of homeostasis and inflammation in the skin and open up novel avenues for the treatment of DLE.