Photo-neuro-immuno-endocrinology: How the ultraviolet radiation regulates the body, brain, and immune system.

Ultraviolet radiation (UVR) is primarily recognized for its detrimental effects such as cancerogenesis, skin aging, eye damage, and autoimmune disorders. With exception of ultraviolet B (UVB) requirement in the production of vitamin D3, the positive role of UVR in modulation of homeostasis is underappreciated. Skin exposure to UVR triggers local responses secondary to the induction of chemical, hormonal, immune, and neural signals that are defined by the chromophores and extent of UVR penetration into skin compartments. These responses are not random and are coordinated by the cutaneous neuro-immuno-endocrine system, which counteracts the action of external stressors and accommodates local homeostasis to the changing environment. The UVR induces electrical, chemical, and biological signals to be sent to the brain, endocrine and immune systems, as well as other central organs, which in concert regulate body homeostasis. To achieve its central homeostatic goal, the UVR-induced signals are precisely computed locally with transmission through nerves or humoral signals release into the circulation to activate and/or modulate coordinating central centers or organs. Such modulatory effects will be dependent on UVA and UVB wavelengths. This leads to immunosuppression, the activation of brain and endocrine coordinating centers, and the modification of different organ functions. Therefore, it is imperative to understand the underlying mechanisms of UVR electromagnetic energy penetration deep into the body, with its impact on the brain and internal organs. Photo-neuro-immuno-endocrinology can offer novel therapeutic approaches in addiction and mood disorders; autoimmune, neurodegenerative, and chronic pain-generating disorders; or pathologies involving endocrine, cardiovascular, gastrointestinal, or reproductive systems.

Epigenetic switch reshapes epithelial progenitor cell signatures and drives inflammatory pathogenesis in hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a complex inflammatory skin disease with undefined mechanistic underpinnings. Here, we investigated HS epithelial cells and demonstrated that HS basal progenitors modulate their lineage restriction and give rise to pathogenic keratinocyte clones, resulting in epidermal hyperproliferation and dysregulated inflammation in HS. When comparing to healthy epithelial stem/progenitor cells, in HS, we identified changes in gene signatures that revolve around the mitotic cell cycle, DNA damage response and repair, as well as cell-cell adhesion and chromatin remodeling. By reconstructing cell differentiation trajectory and CellChat modeling, we identified a keratinocyte population specific to HS. This population is marked by S100A7/8/9 and KRT6 family members, triggering IL1, IL10, and complement inflammatory cascades. These signals, along with HS-specific proinflammatory cytokines and chemokines, contribute to the recruitment of certain immune cells during the disease progression. Furthermore, we revealed a previously uncharacterized role of S100A8 in regulating the local chromatin environment of target loci in HS keratinocytes. Through the integration of genomic and epigenomic datasets, we identified genome-wide chromatin rewiring alongside the switch of transcription factors (TFs), which mediated HS transcriptional profiles. Importantly, we identified numerous clinically relevant inflammatory enhancers and their coordinated TFs in HS basal CD49fhigh cells. The disruption of the S100A enhancer using the CRISPR/Cas9-mediated approach or the pharmacological inhibition of the interferon regulatory transcription factor 3 (IRF3) efficiently reduced the production of HS-associated inflammatory regulators. Our study not only uncovers the plasticity of epidermal progenitor cells in HS but also elucidates the epigenetic mechanisms underlying HS pathogenesis.

Advances in molecular pathogenesis of hidradenitis suppurativa: Dysregulated keratins and ECM signaling.

Hidradenitis suppurativa (HS) is characterized by deep-seated, highly inflamed, and painful lumps/abscesses, fistulae, and sinus tracts that grow extensively deep in the dermis and are highly immunogenic in nature. In about one-third of the HS patients there is strong evidence for the role of γ-secretase mutations along with dysregulated Notch signaling. However, the contribution of dysregulated Notch signaling in HS pathogenesis in relation to hair follicle alterations and hyper-activation of the immune system remains undefined. A genome-wide association study (GWAS), proteomic data and functional investigations of identified sequence variants in HS pathology are not fully revealing. The disease initiation or progression may involve bacterial infection besides intrinsic functional defects in keratinocytes, which may be key to further exacerbate immune cell infiltration and cytokine production in and around the lesional tissue. The absence of a suitable animal model that could fully recapitulate the pathogenesis of HS is a major impediment for proper understanding the underlying mechanisms and development of effective treatments. The presence of extracellular matrix (ECM) degradation products along with dysregulation in keratinocytes and, dermal fibroblasts ultimately affect immune regulation and are various components of HS pathogenesis. Bacterial infection further exacerbates the complexity of the disease progression. While anti-TNFα therapy shows partial efficacy, treatment to cure HS is absent. Multiple clinical trials targeting various cytokines, complement C5a and ECM products are in progress. This review provides state-of-the-art information on these aspects with a focus on dysregulated keratinocyte and immune cells; and role of ECM, and Keratin functions in this regard.

Metabolic activation of tachysterol3 to biologically active hydroxyderivatives that act on VDR, AhR, LXRs, and PPARγ receptors.

CYP11A1 and CYP27A1 hydroxylate tachysterol3 , a photoproduct of previtamin D3 , producing 20S-hydroxytachysterol3 [20S(OH)T3 ] and 25(OH)T3 , respectively. Both metabolites were detected in the human epidermis and serum. Tachysterol3 was also detected in human serum at a concentration of 7.3 ± 2.5 ng/ml. 20S(OH)T3 and 25(OH)T3 inhibited the proliferation of epidermal keratinocytes and dermal fibroblasts and stimulated the expression of differentiation and anti-oxidative genes in keratinocytes in a similar manner to 1,25-dihydroxyvitamin D3 [1,25(OH)2 D3 ]. They acted on the vitamin D receptor (VDR) as demonstrated by image flow cytometry and the translocation of VDR coupled GFP from the cytoplasm to the nucleus of melanoma cells, as well as by the stimulation of CYP24A1 expression. Functional studies using a human aryl hydrocarbon receptor (AhR) reporter assay system revealed marked activation of AhR by 20S(OH)T3 , a smaller effect by 25(OH)T3 , and a minimal effect for their precursor, tachysterol3 . Tachysterol3 hydroxyderivatives showed high-affinity binding to the ligan-binding domain (LBD) of the liver X receptor (LXR) α and ß, and the peroxisome proliferator-activated receptor γ (PPARγ) in LanthaScreen TR-FRET coactivator assays. Molecular docking using crystal structures of the LBDs of VDR, AhR, LXRs, and PPARγ revealed high docking scores for 20S(OH)T3 and 25(OH)T3 , comparable to their natural ligands. The scores for the non-genomic-binding site of the VDR were very low indicating a lack of interaction with tachysterol3 ligands. Our identification of endogenous production of 20S(OH)T3 and 25(OH)T3 that are biologically active and interact with VDR, AhR, LXRs, and PPARγ, provides a new understanding of the biological function of tachysterol3 .

Melatonin and Its Metabolites Can Serve as Agonists on the Aryl Hydrocarbon Receptor and Peroxisome Proliferator-Activated Receptor Gamma.

Melatonin is widely present in Nature. It has pleiotropic activities, in part mediated by interactions with high-affinity G-protein-coupled melatonin type 1 and 2 (MT1 and MT2) receptors or under extreme conditions, e.g., ischemia/reperfusion. In pharmacological concentrations, it is given to counteract the massive damage caused by MT1- and MT2-independent mechanisms. The aryl hydrocarbon receptor (AhR) is a perfect candidate for mediating the latter effects because melatonin has structural similarity to its natural ligands, including tryptophan metabolites and indolic compounds. Using a cell-based Human AhR Reporter Assay System, we demonstrated that melatonin and its indolic and kynuric metabolites act as agonists on the AhR with EC50's between 10-4 and 10-6 M. This was further validated via the stimulation of the transcriptional activation of the CYP1A1 promoter. Furthermore, melatonin and its metabolites stimulated AhR translocation from the cytoplasm to the nucleus in human keratinocytes, as demonstrated by ImageStream II cytometry and Western blot (WB) analyses of cytoplasmic and nuclear fractions of human keratinocytes. These functional analyses are supported by in silico analyses. We also investigated the peroxisome proliferator-activated receptor (PPAR)γ as a potential target for melatonin and metabolites bioregulation. The binding studies using a TR-TFRET kit to assay the interaction of the ligand with the ligand-binding domain (LBD) of the PPARγ showed agonistic activities of melatonin, 6-hydroxymelatonin and N-acetyl-N-formyl-5-methoxykynuramine with EC50's in the 10-4 M range showing significantly lower affinities that those of rosiglitazone, e.g., a 10-8 M range. These interactions were substantiated by stimulation of the luciferase activity of the construct containing PPARE by melatonin and its metabolites at 10-4 M. As confirmed by the functional assays, binding mode predictions using a homology model of the AhR and a crystal structure of the PPARγ suggest that melatonin and its metabolites, including 6-hydroxymelatonin, 5-methoxytryptamine and N-acetyl-N-formyl-5-methoxykynuramine, are excellent candidates to act on the AhR and PPARγ with docking scores comparable to their corresponding natural ligands. Melatonin and its metabolites were modeled into the same ligand-binding pockets (LBDs) as their natural ligands. Thus, functional assays supported by molecular modeling have shown that melatonin and its indolic and kynuric metabolites can act as agonists on the AhR and they can interact with the PPARγ at high concentrations. This provides a mechanistic explanation for previously reported cytoprotective actions of melatonin and its metabolites that require high local concentrations of the ligands to reduce cellular damage under elevated oxidative stress conditions. It also identifies these compounds as therapeutic agents to be used at pharmacological doses in the prevention or therapy of skin diseases.

Neuroendocrine signaling in the skin with a special focus on the epidermal neuropeptides.

The skin, which is comprised of the epidermis, dermis, and subcutaneous tissue, is the largest organ in the human body and it plays a crucial role in the regulation of the body's homeostasis. These functions are regulated by local neuroendocrine and immune systems with a plethora of signaling molecules produced by resident and immune cells. In addition, neurotransmitters, endocrine factors, neuropeptides, and cytokines released from nerve endings play a central role in the skin's responses to stress. These molecules act on the corresponding receptors in an intra-, juxta-, para-, or autocrine fashion. The epidermis as the outer most component of skin forms a barrier directly protecting against environmental stressors. This protection is assured by an intrinsic keratinocyte differentiation program, pigmentary system, and local nervous, immune, endocrine, and microbiome elements. These constituents communicate cross-functionally among themselves and with corresponding systems in the dermis and hypodermis to secure the basic epidermal functions to maintain local (skin) and global (systemic) homeostasis. The neurohormonal mediators and cytokines used in these communications regulate physiological skin functions separately or in concert. Disturbances in the functions in these systems lead to cutaneous pathology that includes inflammatory (i.e., psoriasis, allergic, or atopic dermatitis, etc.) and keratinocytic hyperproliferative disorders (i.e., seborrheic and solar keratoses), dysfunction of adnexal structure (i.e., hair follicles, eccrine, and sebaceous glands), hypersensitivity reactions, pigmentary disorders (vitiligo, melasma, and hypo- or hyperpigmentary responses), premature aging, and malignancies (melanoma and nonmelanoma skin cancers). These cellular, molecular, and neural components preserve skin integrity and protect against skin pathologies and can act as "messengers of the skin" to the central organs, all to preserve organismal survival.

Chemical synthesis, biological activities and action on nuclear receptors of 20S(OH)D3, 20S,25(OH)2D3, 20S,23S(OH)2D3 and 20S,23R(OH)2D3.

New and more efficient routes of chemical synthesis of vitamin D3 (D3) hydroxy (OH) metabolites, including 20S(OH)D3, 20S,23S(OH)2D3 and 20S,25(OH)2D3, that are endogenously produced in the human body by CYP11A1, and of 20S,23R(OH)2D3 were established. The biological evaluation showed that these compounds exhibited similar properties to each other regarding inhibition of cell proliferation and induction of cell differentiation but with subtle and quantitative differences. They showed both overlapping and differential effects on T-cell immune activity. They also showed similar interactions with nuclear receptors with all secosteroids activating vitamin D, liver X, retinoic acid orphan and aryl hydrocarbon receptors in functional assays and also as indicated by molecular modeling. They functioned as substrates for CYP27B1 with enzymatic activity being the highest towards 20S,25(OH)2D3 and the lowest towards 20S(OH)D3. In conclusion, defining new routes for large scale synthesis of endogenously produced D3-hydroxy derivatives by pathways initiated by CYP11A1 opens an exciting era to analyze their common and differential activities in vivo, particularly on the immune system and inflammatory diseases.

Type I Interferons Enhance the Repair of Ultraviolet Radiation-Induced DNA Damage and Regulate Cutaneous Immune Suppression.

Type I interferons (IFNs) are important enhancers of immune responses which are downregulated in human cancers, including skin cancer. Solar ultraviolet (UV) B radiation is a proven environmental carcinogen, and its exposure contributes to the high prevalence of skin cancer. The carcinogenic effects of UV light can be attributed to the formation of cyclobutane pyrimidine dimers (CPD) and errors in the repair and replication of DNA. Treatment with a single dose of UVB (100 mJ/cm2) upregulated IFNα and IFNß in the skin of C57BL/6 mice. IFNα and IFNß were predominantly produced by CD11b+ cells. In mice lacking the type I IFN receptor 1 (IFNAR1), the repair of CPD following cutaneous exposure to a single dose of UVB (100 mJ/cm2) was decreased. UVB induced the expression of the DNA repair gene xeroderma pigmentosum A (XPA) in wild-type (WT) mice. In contrast, such treatment in IFNAR1 (IFNAR1-/-) mice downregulated XPA. A local UVB regimen consisting of UVB radiation (150 mJ/cm2) for 4 days followed by sensitization with hapten 2,4, dinitrofluorobenzene (DNFB) resulted in significant suppression of immune responses in both WT and IFNAR1-/- mice. However, there were significantly higher CD4+CD25+Foxp3+ regulatory T-cells in the draining lymph nodes of IFNAR1-/- mice in comparison to WT mice. Overall, our studies reveal a previously unknown action of type I IFNs in the repair of photodamage and the prevention of UVB-induced immune suppression.

Neutrophil-Derived S100A8/A9 Amplify Granulopoiesis After Myocardial Infarction.

BACKGROUND: Myocardial infarction (MI) triggers myelopoiesis, resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear. METHODS: Using a mouse model of the permanent ligation of the left anterior descending artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of the acute inflammatory response and the underlying signaling pathways. Using a combination of genetic and pharmacological strategies, we identified the sequelae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indexes of neutrophilia with major adverse cardiovascular events was studied in a cohort of patients with acute MI. RESULTS: Induction of MI results in rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll-like receptor 4 and prime the nod-like receptor family pyrin domain-containing 3 inflammasome in naïve neutrophils and promote interleukin-1ß secretion. The released interleukin-1ß interacts with its receptor (interleukin 1 receptor type 1) on hematopoietic stem and progenitor cells in the bone marrow and stimulates granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and their downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome, higher neutrophil count on admission and after revascularization correlates positively with major adverse cardiovascular disease outcomes. CONCLUSIONS: Our study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response after myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or their downstream mediators (eg, nod-like receptor family pyrin domain-containing 3 inflammasome, interleukin-1ß) in neutrophils suppress granulopoiesis and may improve cardiac function in patients with acute coronary syndrome.

Vitamin D and lumisterol novel metabolites can inhibit SARS-CoV-2 replication machinery enzymes.

Vitamin D deficiency significantly correlates with the severity of SARS-CoV-2 infection. Molecular docking-based virtual screening studies predict that novel vitamin D and related lumisterol hydroxymetabolites are able to bind to the active sites of two SARS-CoV-2 transcription machinery enzymes with high affinity. These enzymes are the main protease (Mpro) and RNA-dependent RNA polymerase (RdRP), which play important roles in viral replication and establishing infection. Based on predicted binding affinities and specific interactions, we identified 10 vitamin D3 (D3) and lumisterol (L3) analogs as likely binding partners of SARS-CoV-2 Mpro and RdRP and, therefore, tested their ability to inhibit these enzymes. Activity measurements demonstrated that 25(OH)L3, 24(OH)L3, and 20(OH)7DHC are the most effective of the hydroxymetabolites tested at inhibiting the activity of SARS-CoV-2 Mpro causing 10%-19% inhibition. These same derivatives as well as other hydroxylumisterols and hydroxyvitamin D3 metabolites inhibited RdRP by 50%-60%. Thus, inhibition of these enzymes by vitamin D and lumisterol metabolites may provide a novel approach to hindering the SARS-CoV-2 infection.NEW & NOTEWORTHY Active forms of vitamin D and lumisterol can inhibit SARS-CoV-2 replication machinery enzymes, which indicates that novel vitamin D and lumisterol metabolites are candidates for antiviral drug research.

Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis.

BACKGROUND: Follicular regulatory T (TFR) cells are essential for the regulation of germinal center (GC) response and humoral self-tolerance. Dysregulated follicular helper T (TFH) cell-GC-antibody (Ab) response secondary to dysfunctional TFR cells is the root of an array of autoimmune disorders. The contribution of TFR cells to the pathogenesis of multiple sclerosis (MS) and murine experimental autoimmune encephalomyelitis (EAE) remains largely unclear. METHODS: To determine the impact of dysregulated regulatory T cells (Tregs), TFR cells, and Ab responses on EAE, we compared the MOG-induced EAE in mice with a FoxP3-specific ablation of the transcription factor Blimp1 to control mice. In vitro co-culture assays were used to understand how Tregs and Ab regulate the activity of microglia and central nervous system (CNS)-infiltrating myeloid cells. RESULTS: Mice with a FoxP3-specific deletion of Blimp1 developed severe EAE and failed to recover compared to control mice, reflecting conversion of Tregs into interleukin (IL)-17A/granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing effector T cells associated with increased TFH-Ab responses, more IgE deposition in the CNS, and inability to regulate CNS CD11b+ myeloid cells. Notably, serum IgE titers were positively correlated with EAE scores, and culture of CNS CD11b+ cells with sera from these EAE mice enhanced their activation, while transfer of Blimp1-deficient TFR cells promoted Ab production, activation of CNS CD11b+ cells, and EAE. CONCLUSIONS: Blimp1 is essential for the maintenance of TFR cells and Ab responses in EAE. Dysregulated TFR cells and Ab responses promote CNS autoimmunity.

Extra-adrenal glucocorticoid biosynthesis: implications for autoimmune and inflammatory disorders.

Glucocorticoid synthesis is a complex, multistep process that starts with cholesterol being delivered to the inner membrane of mitochondria by StAR and StAR-related proteins. Here its side chain is cleaved by CYP11A1 producing pregnenolone. Pregnenolone is converted to cortisol by the enzymes 3-ßHSD, CYP17A1, CYP21A2, and CYP11B1. Glucocorticoids play a critical role in the regulation of the immune system and exert their action through the glucocorticoid receptor (GR). Although corticosteroids are primarily produced in the adrenal gland, they can also be produced in a number of extra-adrenal tissue including the immune system, skin, brain, and intestine. Glucocorticoid production is regulated by ACTH, CRH, and cytokines such as IL-1, IL-6, and TNFα. The bioavailability of cortisol is also dependent on its interconversion to cortisone, which is inactive, by 11ßHSD1/2. Local and systemic glucocorticoid biosynthesis can be stimulated by ultraviolet B, explaining its immunosuppressive activity. In this review, we want to emphasize that dysregulation of extra-adrenal glucocorticoid production can play a key role in a variety of autoimmune diseases including multiple sclerosis (MS), lupus erythematosus (LE), rheumatoid arthritis (RA), and skin inflammatory disorders such as psoriasis and atopic dermatitis (AD). Further research on local glucocorticoid production and its bioavailability may open doors into new therapies for autoimmune diseases.

COVID-19 and Vitamin D: A lesson from the skin.

The negative outcomes of COVID-19 diseases respiratory distress (ARDS) and the damage to other organs are secondary to a "cytokine storm" and to the attendant oxidative stress. Active hydroxyl forms of vitamin D are anti-inflammatory, induce antioxidative responses, and stimulate innate immunity against infectious agents. These properties are shared by calcitriol and the CYP11A1-generated non-calcemic hydroxyderivatives. They inhibit the production of pro-inflammatory cytokines, downregulate NF-κΒ, show inverse agonism on RORγ and counteract oxidative stress through the activation of NRF-2. Therefore, a direct delivery of hydroxyderivatives of vitamin D deserves consideration in the treatment of COVID-19 or ARDS of different aetiology. We also recommend treatment of COVID-19 patients with high-dose vitamin D since populations most vulnerable to this disease are likely vitamin D deficient and patients are already under supervision in the clinics. We hypothesize that different routes of delivery (oral and parenteral) will have different impact on the final outcome.

Hydroxylumisterols, Photoproducts of Pre-Vitamin D3, Protect Human Keratinocytes against UVB-Induced Damage.

Lumisterol (L3) is a stereoisomer of 7-dehydrocholesterol and is produced through the photochemical transformation of 7-dehydrocholesteol induced by high doses of UVB. L3 is enzymatically hydroxylated by CYP11A1, producing 20(OH)L3, 22(OH)L3, 20,22(OH)2L3, and 24(OH)L3. Hydroxylumisterols function as reverse agonists of the retinoic acid-related orphan receptors α and γ (RORα/γ) and can interact with the non-genomic binding site of the vitamin D receptor (VDR). These intracellular receptors are mediators of photoprotection and anti-inflammatory activity. In this study, we show that L3-hydroxyderivatives significantly increase the expression of VDR at the mRNA and protein levels in keratinocytes, both non-irradiated and after UVB irradiation. L3-hydroxyderivatives also altered mRNA and protein levels for RORα/γ in non-irradiated cells, while the expression was significantly decreased in UVB-irradiated cells. In UVB-irradiated keratinocytes, L3-hydroxyderivatives inhibited nuclear translocation of NFκB p65 by enhancing levels of IκBα in the cytosol. This anti-inflammatory activity mediated by L3-hydroxyderivatives through suppression of NFκB signaling resulted in the inhibition of the expression of UVB-induced inflammatory cytokines, including IL-17, IFN-γ, and TNF-α. The L3-hydroxyderivatives promoted differentiation of UVB-irradiated keratinocytes as determined from upregulation of the expression at the mRNA of involucrin (IVL), filaggrine (FLG), and keratin 14 (KRT14), downregulation of transglutaminase 1 (TGM1), keratins including KRT1, and KRT10, and stimulation of ILV expression at the protein level. We conclude that CYP11A1-derived hydroxylumisterols are promising photoprotective agents capable of suppressing UVB-induced inflammatory responses and restoring epidermal function through targeting the VDR and RORs.

TßRIII is induced by TCR signaling and downregulated in FoxP3+ regulatory T cells.

TGF-ß type III receptor (TßRIII) is a co-receptor for TGFß family members required for high-affinity binding of these ligands to their receptors, potentiating their cellular functions. TGF-ßs, Bone Morphogenetic Proteins (BMP2/4) and Inhibins/Activins regulate different checkpoints during T cell differentiation. We have previously reported that TßRIII modulates T cell development by protecting developing thymocytes from apoptosis, however the role of this co-receptor in peripheral lymphocytes still remains elusive. Here we describe a detailed characterization of TßRIII expression in murine and human lymphocyte subpopulations demonstrating that this co-receptor is significantly expressed in T but not B lymphocytes and among them, preferentially expressed on naïve and central memory T cells. TßRIII was upregulated after TCR stimulation, in parallel to other early activation markers. In contrast, natural and induced Tregs downregulated TßRIII in association with FoxP3 upregulation. Finally, anti-TßRIII blocking experiments demonstrated that TßRIII promotes TGFß-dependent iTreg conversion in vitro, and suggest that this co-receptor may be involved in modulating peripheral T cell tolerance and could be considered as a potential target to boost T cell immune responses.

Inhibition of System Xc(-) Transporter Attenuates Autoimmune Inflammatory Demyelination.

T cell infiltration into the CNS is a significant underlying pathogenesis in autoimmune inflammatory demyelinating diseases. Several lines of evidence suggest that glutamate dysregulation in the CNS is an important consequence of immune cell infiltration in neuroinflammatory demyelinating diseases; yet, the causal link between inflammation and glutamate dysregulation is not well understood. A major source of glutamate release during oxidative stress is the system Xc(-) transporter; however, this mechanism has not been tested in animal models of autoimmune inflammatory demyelination. We find that pharmacological and genetic inhibition of system Xc(-) attenuates chronic and relapsing-remitting experimental autoimmune encephalomyelitis (EAE). Remarkably, pharmacological blockade of system Xc(-) 7 d after induction of EAE attenuated T cell infiltration into the CNS, but not T cell activation in the periphery. Mice harboring a Slc7a11 (xCT) mutation that inactivated system Xc(-) were resistant to EAE, corroborating a central role for system Xc(-) in mediating immune cell infiltration. We next examined the role of the system Xc(-) transporter in the CNS after immune cell infiltration. Pharmacological inhibitors of the system Xc(-) transporter administered during the first relapse in a SJL animal model of relapsing-remitting EAE abrogated clinical disease, inflammation, and myelin loss. Primary coculture studies demonstrate that myelin-specific CD4(+) Th1 cells provoke microglia to release glutamate via the system Xc(-) transporter, causing excitotoxic death to mature myelin-producing oligodendrocytes. Taken together, these studies support a novel role for the system Xc(-) transporter in mediating T cell infiltration into the CNS as well as promoting myelin destruction after immune cell infiltration in EAE.

Therapeutic efficacy of suppressing the Jak/STAT pathway in multiple models of experimental autoimmune encephalomyelitis.

Pathogenic Th cells and myeloid cells are involved in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. The JAK/STAT pathway is used by numerous cytokines for signaling and is critical for development, regulation, and termination of immune responses. Dysregulation of the JAK/STAT pathway has pathological implications in autoimmune and neuroinflammatory diseases. Many of the cytokines involved in MS/EAE, including IL-6, IL-12, IL-23, IFN-γ, and GM-CSF, use the JAK/STAT pathway to induce biological responses. Thus, targeting JAKs has implications for treating autoimmune inflammation of the brain. We have used AZD1480, a JAK1/2 inhibitor, to investigate the therapeutic potential of inhibiting the JAK/STAT pathway in models of EAE. AZD1480 treatment inhibits disease severity in myelin oligodendrocyte glycoprotein-induced classical and atypical EAE models by preventing entry of immune cells into the brain, suppressing differentiation of Th1 and Th17 cells, deactivating myeloid cells, inhibiting STAT activation in the brain, and reducing expression of proinflammatory cytokines and chemokines. Treatment of SJL/J mice with AZD1480 delays disease onset of PLP-induced relapsing-remitting disease, reduces relapses and diminishes clinical severity. AZD1480 treatment was also effective in reducing ongoing paralysis induced by adoptive transfer of either pathogenic Th1 or Th17 cells. In vivo AZD1480 treatment impairs both the priming and expansion of T cells and attenuates Ag presentation functions of myeloid cells. Inhibition of the JAK/STAT pathway has clinical efficacy in multiple preclinical models of MS, suggesting the feasibility of the JAK/STAT pathway as a target for neuroinflammatory diseases.

Janus-like effects of type I interferon in autoimmune diseases.

In multiple sclerosis, type I interferon (IFN) is considered immune-modulatory, and recombinant forms of IFN-ß are the most prescribed treatment for this disease. This is in contrast to most other autoimmune disorders, because type I IFN contributes to the pathologies. Even within the relapsing-remitting multiple sclerosis (RRMS) population, 30-50% of MS patients are non-responsive to this treatment, and it consistently worsens neuromyelitis optica, a disease similar to RRMS. In this article, we discuss the recent advances in the field of autoimmunity and introduce the theory explain how type I IFNs can be pro-inflammatory in disease that is predominantly driven by a Th17 response and are therapeutic when disease is predominantly Th1.