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Article ; Online: Electrophilic nitro-fatty acids suppress psoriasiform dermatitis

Peng Wang / Meaghan E. Killeen / Tina L. Sumpter / Laura K. Ferris / Louis D. Falo, Jr. / Bruce A. Freeman / Francisco J. Schopfer / Alicia R. Mathers

Redox Biology, Vol 43, Iss , Pp 101987- (2021)

STAT3 inhibition as a contributory mechanism

2021

Abstract: Psoriasis is a chronic inflammatory skin disease with no cure. Although the origin of psoriasis and its underlying pathophysiology remain incompletely understood, inflammation is a central mediator of disease progression. In this regard, electrophilic ... ...

Abstract	Psoriasis is a chronic inflammatory skin disease with no cure. Although the origin of psoriasis and its underlying pathophysiology remain incompletely understood, inflammation is a central mediator of disease progression. In this regard, electrophilic nitro-fatty acids (NO2–FAs) exert potent anti-inflammatory effects in several in vivo murine models of inflammatory diseases, such as chronic kidney disease and cardiovascular disease. To examine the therapeutic potential of NO2–FAs on psoriasiform dermatitis, we employed multiple murine models of psoriasis. Our studies demonstrate that oral treatment with nitro oleic acid (OA-NO2) has both preventative and therapeutic effects on psoriasiform inflammation. In line with this finding, oral OA-NO2 downregulated the production of inflammatory cytokines in the skin. In vitro experiments demonstrate that OA-NO2 decreased both basal IL-6 levels and IL-17A-induced expression of IL-6 in human dermal fibroblasts through the inhibition of NF-κB phosphorylation. Importantly, OA-NO2 diminished STAT3 phosphorylation and nuclear translocation via nitroalkylation of STAT3, which inhibited keratinocyte proliferation. Overall, our results affirm the critical role of both NF-κB and STAT3 in the incitement of psoriasiform dermatitis and highlight the pharmacologic potential of small molecule nitroalkenes for the treatment of cutaneous inflammatory diseases, such as psoriasis.
Keywords	Electrophilic fatty acids ; Psoriasis ; Nitro oleic acid ; Cutaneous inflammation ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2021-07-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Dysregulation of the TOX-RUNX3 pathway in cutaneous T-cell lymphoma.

Dulmage, Brittany O / Akilov, Oleg / Vu, John R / Falo, Louis D / Geskin, Larisa J

Oncotarget

2019 Volume 10, Issue 33, Page(s) 3104–3113

Abstract: Studies have examined gene expression changes in Sézary syndrome (SS), but disease pathogenesis remains largely unknown, and diagnosis and treatment are difficult. ...

Abstract	Studies have examined gene expression changes in Sézary syndrome (SS), but disease pathogenesis remains largely unknown, and diagnosis and treatment are difficult.
Language	English
Publishing date	2019-05-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.5742
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Preventative Vaccines for Zika Virus Outbreak

Eun Kim / Geza Erdos / Shaohua Huang / Thomas Kenniston / Louis D. Falo Jr. / Andrea Gambotto

EBioMedicine, Vol 13, Iss C, Pp 315-

Preliminary Evaluation

2016 Volume 320

Abstract: Since it emerged in Brazil in May 2015, the mosquito-borne Zika virus (ZIKV) has raised global concern due to its association with a significant rise in the number of infants born with microcephaly and neurological disorders such as Guillain-Barré ... ...

Abstract	Since it emerged in Brazil in May 2015, the mosquito-borne Zika virus (ZIKV) has raised global concern due to its association with a significant rise in the number of infants born with microcephaly and neurological disorders such as Guillain-Barré syndrome. We developed prototype subunit and adenoviral-based Zika vaccines encoding the extracellular portion of the ZIKV envelope gene (E) fused to the T4 fibritin foldon trimerization domain (Efl). The subunit vaccine was delivered intradermally through carboxymethyl cellulose microneedle array (MNA). The immunogenicity of these two vaccines, named Ad5.ZIKV-Efl and ZIKV-rEfl, was tested in C57BL/6 mice. Prime/boost immunization regimen was associated with induction of a ZIKV-specific antibody response, which provided neutralizing immunity. Moreover, protection was evaluated in seven-day-old pups after virulent ZIKV intraperitoneal challenge. Pups born to mice immunized with Ad5.ZIKV-Efl were all protected against lethal challenge infection without weight loss or neurological signs, while pups born to dams immunized with MNA-ZIKV-rEfl were partially protected (50%). No protection was seen in pups born to phosphate buffered saline-immunized mice. This study illustrates the preliminary efficacy of the E ZIKV antigen vaccination in controlling ZIKV infectivity, providing a promising candidate vaccine and antigen format for the prevention of Zika virus disease.
Keywords	Zika virus ; ZIKV-E ; Vaccine ; Microneedles ; Adenovirus ; Medicine ; R
Subject code	570
Language	English
Publishing date	2016-11-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Microneedle array delivered recombinant coronavirus vaccines

Eun Kim / Geza Erdos / Shaohua Huang / Thomas W. Kenniston / Stephen C. Balmert / Cara Donahue Carey / V. Stalin Raj / Michael W. Epperly / William B. Klimstra / Bart L. Haagmans / Emrullah Korkmaz / Louis D. Falo, Jr. / Andrea Gambotto

EBioMedicine, Vol 55, Iss , Pp - (2020)

Immunogenicity and rapid translational development

2020

Abstract: Background: Coronaviruses pose a serious threat to global health as evidenced by Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and COVID-19. SARS Coronavirus (SARS-CoV), MERS Coronavirus (MERS-CoV), and the novel ... ...

Abstract	Background: Coronaviruses pose a serious threat to global health as evidenced by Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and COVID-19. SARS Coronavirus (SARS-CoV), MERS Coronavirus (MERS-CoV), and the novel coronavirus, previously dubbed 2019-nCoV, and now officially named SARS-CoV-2, are the causative agents of the SARS, MERS, and COVID-19 disease outbreaks, respectively. Safe vaccines that rapidly induce potent and long-lasting virus-specific immune responses against these infectious agents are urgently needed. The coronavirus spike (S) protein, a characteristic structural component of the viral envelope, is considered a key target for vaccines for the prevention of coronavirus infection. Methods: We first generated codon optimized MERS-S1 subunit vaccines fused with a foldon trimerization domain to mimic the native viral structure. In variant constructs, we engineered immune stimulants (RS09 or flagellin, as TLR4 or TLR5 agonists, respectively) into this trimeric design. We comprehensively tested the pre-clinical immunogenicity of MERS-CoV vaccines in mice when delivered subcutaneously by traditional needle injection, or intracutaneously by dissolving microneedle arrays (MNAs) by evaluating virus specific IgG antibodies in the serum of vaccinated mice by ELISA and using virus neutralization assays. Driven by the urgent need for COVID-19 vaccines, we utilized this strategy to rapidly develop MNA SARS-CoV-2 subunit vaccines and tested their pre-clinical immunogenicity in vivo by exploiting our substantial experience with MNA MERS-CoV vaccines. Findings: Here we describe the development of MNA delivered MERS-CoV vaccines and their pre-clinical immunogenicity. Specifically, MNA delivered MERS-S1 subunit vaccines elicited strong and long-lasting antigen-specific antibody responses. Building on our ongoing efforts to develop MERS-CoV vaccines, promising immunogenicity of MNA-delivered MERS-CoV vaccines, and our experience with MNA fabrication and delivery, including ...
Keywords	Subunit vaccines ; Trimerization ; Microneedle array ; MERS-CoV S1 ; SARS-CoV-2 ; COVID-19 ; Medicine ; R ; Medicine (General) ; R5-920
Subject code	572
Language	English
Publishing date	2020-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Neurokinin-1 Receptor Signaling Is Required for Efficient Ca2+ Flux in T-Cell-Receptor-Activated T Cells

Adrian E. Morelli / Tina L. Sumpter / Darling M. Rojas-Canales / Mohna Bandyopadhyay / Zhizhao Chen / Olga Tkacheva / William J. Shufesky / Callen T. Wallace / Simon C. Watkins / Alexandra Berger / Christopher J. Paige / Louis D. Falo, Jr. / Adriana T. Larregina

Cell Reports, Vol 30, Iss 10, Pp 3448-3465.e

2020 Volume 8

Abstract: Summary: Efficient Ca2+ flux induced during cognate T cell activation requires signaling the T cell receptor (TCR) and unidentified G-protein-coupled receptors (GPCRs). T cells express the neurokinin-1 receptor (NK1R), a GPCR that mediates Ca2+ flux in ... ...

Abstract	Summary: Efficient Ca2+ flux induced during cognate T cell activation requires signaling the T cell receptor (TCR) and unidentified G-protein-coupled receptors (GPCRs). T cells express the neurokinin-1 receptor (NK1R), a GPCR that mediates Ca2+ flux in excitable and non-excitable cells. However, the role of the NK1R in TCR signaling remains unknown. We show that the NK1R and its agonists, the neuropeptides substance P and hemokinin-1, co-localize within the immune synapse during cognate activation of T cells. Simultaneous TCR and NK1R stimulation is necessary for efficient Ca2+ flux and Ca2+-dependent signaling that sustains the survival of activated T cells and helper 1 (Th1) and Th17 bias. In a model of contact dermatitis, mice with T cells deficient in NK1R or its agonists exhibit impaired cellular immunity, due to high mortality of activated T cells. We demonstrate an effect of the NK1R in T cells that is relevant for immunotherapies based on pro-inflammatory neuropeptides and its receptors. : The neurokinin 1 receptor (NK1R) induces Ca2+ flux in excitable cells. Here, Morelli et al. show that NK1R signaling in T cells promotes optimal Ca2+ flux triggered by TCR stimulation, which is necessary to sustain T cell survival and the efficient Th1- and Th17-based immunity that is relevant for immunotherapies based on pro-inflammatory neuropeptides. Keywords: neurokinin-1 receptor, T cell receptor, G-protein-coupled receptors, Ca2+ flux, Gαq/11, substance P, hemokinin-1, T cell activation, T cell bias, T cell survival
Keywords	Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2020-03-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: In vivo induction of regulatory T cells promotes allergen tolerance and suppresses allergic contact dermatitis.

Balmert, Stephen C / Donahue, Cara / Vu, John R / Erdos, Geza / Falo, Louis D / Little, Steven R

Journal of controlled release : official journal of the Controlled Release Society

2017 Volume 261, Page(s) 223–233

Abstract: Allergic contact dermatitis (ACD) is a common T-cell mediated inflammatory skin condition, characterized by an intensely pruritic rash at the site of contact with allergens like poison ivy or nickel. Current clinical treatments use topical ... ...

Abstract	Allergic contact dermatitis (ACD) is a common T-cell mediated inflammatory skin condition, characterized by an intensely pruritic rash at the site of contact with allergens like poison ivy or nickel. Current clinical treatments use topical corticosteroids, which broadly and transiently suppress inflammation and symptoms of ACD, but fail to address the underlying immune dysfunction. Here, we present an alternative therapeutic approach that teaches the immune system to tolerate contact allergens by expanding populations of naturally suppressive allergen-specific regulatory T cells (Tregs). Specifically, biodegradable poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PEG-PLGA) microparticles were engineered to release TGF-β1, Rapamycin, and IL-2, to locally sustain a microenvironment that promotes Treg differentiation. By expanding allergen-specific Tregs and reducing pro-inflammatory effector T cells, these microparticles inhibited destructive hypersensitivity responses to subsequent allergen exposure in an allergen-specific manner, effectively preventing or reversing ACD in previously sensitized mice. Ultimately, this approach to in vivo Treg induction could also enable novel therapies for transplant rejection and autoimmune diseases.
MeSH term(s)	Allergens/immunology ; Animals ; Cell Differentiation ; Dermatitis, Allergic Contact/immunology ; Dermatitis, Allergic Contact/therapy ; Female ; Immune Tolerance ; Interleukin-2/administration & dosage ; Interleukin-2/immunology ; Mice ; Mice, Congenic ; Mice, Inbred C57BL ; Mice, Transgenic ; Polyesters/chemistry ; Polyethylene Glycols/chemistry ; Sirolimus/administration & dosage ; Sirolimus/immunology ; T-Lymphocytes, Regulatory/immunology ; Transforming Growth Factor beta1/administration & dosage ; Transforming Growth Factor beta1/immunology
Chemical Substances	Allergens ; Interleukin-2 ; Polyesters ; Transforming Growth Factor beta1 ; polyethylene glycol-poly(lactide-co-glycolide) ; Polyethylene Glycols (3WJQ0SDW1A) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2017-07-08
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2017.07.006
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Article ; Online: Skin Immunization Obviates Alcohol-Related Immune Dysfunction

Rhonda M. Brand / John Mark Stottlemyer / Rachel A. Cline / Cara Donahue / Jaideep Behari / Louis D. Falo Jr.

Biomolecules, Vol 5, Iss 4, Pp 3009-

2015 Volume 3028

Abstract: Alcoholics suffer from immune dysfunction that can impede vaccine efficacy. If ethanol (EtOH)-induced immune impairment is in part a result of direct exposure of immune cells to EtOH, then reduced levels of exposure could result in less immune ... ...

Abstract	Alcoholics suffer from immune dysfunction that can impede vaccine efficacy. If ethanol (EtOH)-induced immune impairment is in part a result of direct exposure of immune cells to EtOH, then reduced levels of exposure could result in less immune dysfunction. As alcohol ingestion results in lower alcohol levels in skin than blood, we hypothesized that the skin immune network may be relatively preserved, enabling skin-targeted immunizations to obviate the immune inhibitory effects of alcohol consumption on conventional vaccines. We employed the two most common chronic EtOH mouse feeding models, the liver-damaging Lieber-DeCarli (LD) and liver-sparing Meadows-Cook (MC) diets, to examine the roles of EtOH and/or EtOH-induced liver dysfunction on alcohol related immunosuppression. Pair-fed mice were immunized against the model antigen ovalbumin (OVA) by DNA immunization or against flu by administering the protein-based influenza vaccine either systemically (IV, IM), directly to liver (hydrodynamic), or cutaneously (biolistic, ID). We measured resulting tissue EtOH levels, liver stress, regulatory T cell (Treg), and myeloid-derived suppressor cell (MDSC) populations. We compared immune responsiveness by measuring delayed-type hypersensitivity (DTH), antigen-specific cytotoxic T lymphocyte (CTL), and antibody induction as a function of delivery route and feeding model. We found that, as expected, and independent of the feeding model, EtOH ingestion inhibits DTH, CTL lysis, and antigen-specific total IgG induced by traditional systemic vaccines. On the other hand, skin-targeted vaccines were equally immunogenic in alcohol-exposed and non-exposed subjects, suggesting that cutaneous immunization may result in more efficacious vaccination in alcohol-ingesting subjects.
Keywords	skin immunity ; vaccination ; alcohol ; ethanol ; intradermal immunization ; skin ; Lieber-DeCarli ; Meadows-Cook ; Biology (General) ; QH301-705.5 ; Science ; Q
Subject code	616
Language	English
Publishing date	2015-11-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Comparative proteomic analysis reveals unique tumor protein composition among the melanoma subtypes pure desmoplastic and superficial spreading.

Schowalter, Michael K / Dulmage, Brittany O / Ho, Jonhan / Vu, John R / Falo, Louis D / Geskin, Larisa J

Melanoma research

2014 Volume 24, Issue 4, Page(s) 397–400

Abstract: The U.S. death rate for melanoma has not decreased, despite the use of depth at biopsy and sentinel lymph node status to determine the risk of metastasis. Additional prognostic indicators and therapeutic targets are required, and identification of ... ...

Abstract	The U.S. death rate for melanoma has not decreased, despite the use of depth at biopsy and sentinel lymph node status to determine the risk of metastasis. Additional prognostic indicators and therapeutic targets are required, and identification of candidate proteins was the goal of this study. We utilized comparative mass spectrometry to compare five samples of each of two forms of melanoma, pure desmoplastic, which by depth at diagnosis has a favorable prognosis, and superficial spreading. Ontological analysis was applied to identify proteins and networks that were increased in one of the two subtypes. Analysis revealed a protein signature increase in pure desmoplastic melanoma associated with cell-to-cell binding and a signature increase in superficial spreading melanoma responsible for the cellular stress response including a constellation of heat shock proteins. The two subtypes of melanoma compared in this study have two unique protein compositions that correlate with their phenotypes. Further validation studies are warranted to evaluate the utility of identified proteins as prognostic markers and therapeutic targets.
MeSH term(s)	Adult ; Disease-Free Survival ; Humans ; Melanoma/metabolism ; Melanoma/pathology ; Neoplasm Proteins/analysis ; Neoplasm Proteins/metabolism ; Prognosis ; Proteomics/methods ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology ; Melanoma, Cutaneous Malignant
Chemical Substances	Neoplasm Proteins
Language	English
Publishing date	2014-04-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1095779-0
ISSN	1473-5636 ; 0960-8931
ISSN (online)	1473-5636
ISSN	0960-8931
DOI	10.1097/CMR.0000000000000070
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