key: cord-0948234-o0a655tm
authors: Mitamura, Y.; Schulz, D.; Kolm, I.; Oro, S.; Levesque, M.; Maverakis, E.; Akdis, C.; Brüggen, M.
title: 011 Systemic hyperinflammation as a driver of maculopapular drug exanthema in severely ill COVID-19 patients?
date: 2021-05-31
journal: Journal of Investigative Dermatology
DOI: 10.1016/j.jid.2021.02.027
sha: a8fcd7a8c75348ccb946a31deb5e03eb2e5a5a1c
doc_id: 948234
cord_uid: o0a655tm

nan

Health supplement Spirulina induces inflammatory cytokine production via monocyte derived dendritic cells and classical monocyte activation in Dermatomyositis D Diaz 1,2 , C Bax 1,2 , Y Li 1,2 , M Grinnell 1,2 , T Vazquez 1,2 , E Keyes 1,2 and V Werth 1,2 1 Dermatology, Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania, United States and 2 Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States The popular herbal supplement Spirulina has previously been shown to stimulate inflammatory cytokine production in Dermatomyositis (DM) patients in vitro. We sought to evaluate whether Spirulina's immunostimulatory effects differ in healthy controls (HCs) compared to DM. We performed ELISA on Spirulina stimulated HC and DM PBMC supernatants, demonstrating similar effects in both HCs and DM with Spirulina significantly increasing TNFa and IFNg levels. Inhibition of TLR4 or TBK1 significantly decreased Spirulina's immunostimulatory effects on both TNFa (p<0.0001) and IFNg (p<0.05) at 0.3 mg/ml Spirulina. Using flow cytometry, we investigated Spirulina's immunostimulatory effects at the cellular level, demonstrating that for TNFa and IFNg secretion, Spirulina has the greatest effect on monocytederived dendritic cells (moDC) and classical monocytes (CM) in DM patients. With stimulation at 0, 0.3, and 1 mg/mL of Spirulina, the percent of moDCs secreting IFNg increased from a mean (SEM) of 1.01% to 96.40% and 96.90% (1.80) (p<0.0001), respectively and the median fluorescent intensity (MFI) increased similarly. (n ¼ 3, p <0.01). The mean percent of CMs secreting IFNg also increased (p<0.0001), and pre-treatment with TLR4 inhibitor suppressed CM activation (p<0.05). Moreover, the MFI of CMs secreting IFNg increased significantly (p<0.005). TLR4 or TBK1 inhibition decreased MFI for both moDC and CM's (p<0.05 and p<0.001, respectively).TNFa+ moDCs increased from 1.14% of total moDCs with no stimulation to 49.10% (12.4) at 0.3 mg/mL Spirulina (p<0.05). TLR4 and TBK1 inhibition suppressed the percentage of Spirulina-induced moDCs secreting TNFa (p<0.05); TLR4 inhibition trended towards significance in CMs (p¼0.053). These data demonstrate that Spirulina induces CM and moDC activation in DM, likely via TLR4 or TBK1 activation.

Multiplexed skin immunophenotyping of new-onset dermatomyositis lesions following first time use of Spirulina platensis T Vazquez 1,2 , J Patel 1,2 , C Bax 1,2 , D Diaz 1,2 , M Grinnell 1,2 , E Keyes 1,2 , M Sharma 1,2 and V Werth 1,2 1 Corporal Michael J. Crescenz VAMC, Philadelphia, Pennsylvania, United States and 2 Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States The rise in the use of natural supplements to improve wellbeing and boost immune function has led to a rise in the use of herbal products such as Spirulina platensis. Our group has previously shown that Spirulina use is temporally associated with both new-onset and acute exacerbations of dermatomyositis (DM). We have also previously shown that Spirulina is capable of activating the TLR4 and STING pathways, as well as inducing TNFa, IFNb, and IFNg production. Here, we sought to characterize the cutaneous inflammatory infiltrate in Spirulina-induced dermatomyositis (Spir-DM). We performed high-plex, in situ, single-cell level analysis of lesional biopsies of DM and Spir-DM skin using Imaging Mass Cytometry (IMC). We utilized two separate panels of 37 metal-conjugated antibodies against various surface markers, intracellular cytokines, and phosphorylated signaling molecules of interest. Significance was determined by the Mann-Whitney test. Our data show similar dermal counts of 17 cell populations, including macrophages, dendritic cells, T and B cells (p>0.05). Total cytokine and activated pathway signal intensity was also similar between both groups for type I IFN and JAK-STAT pathways (p>0.05). Using a heatmap of cell types plotted against intracellular markers, we sought to identify cytokines or inflammatory pathways that may be differentially up-or down-regulated in Spir-DM patients. We similarly found no significant differences at the canonical cell-type level; however, there was notable heterogeneity in both groups. While the precise trigger for autoimmunity induced by Spirulina requires further interrogation, we believe these data suggest Spirulina induces immunophenotypically similar DM when compared to DM triggered by other causes, with little difference in the inflammatory infiltrate.

Hyperthermia controls DAB2 transcription in macrophage through inducing the separation of cJun and cFos heterodimers S Zhao, R Qi, X Gao and H Chen The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China Sporotrichosis is an emergent subcutaneous mycosis of humans and some animals caused by dimorphic fungi of the Sporothrix schenckii. Hyperthermia can effectively treat sporotrichosis by regulating the phenotypic regulation of macrophages which is critical for controlling tissue inflammation and resolution. The adaptor protein disabled homolog 2 (DAB2), a regulator of phenotypic polarization in macrophages, have been identified to inhibit an inflammatory phenotype of the macrophages. However, whether and how hyperthermia act on the immune regulation of macrophages through DAB2 needs more research and complement. In this study, mouse bone marrow extracted primary macrophages (BMDMs) and cell line ANA-1 were used to investigate the regulation of DAB2 gene transcription by hyperthermia in vitro. Immunofluorescence was used to examine sub-localization of AP-1 complex within the cells under the 42 C conditions. Chromatin immunoprecipitation was used to detect whether 42 C stimulation affect the binding of AP-1complex to DAB2 gene. Conditional DAB2 knockout mice were used to evaluate the role of DAB2 in Sporotrichosis. Our results show that 42 C stimulation downregulated the expression of c-Jun and c-Fos, and led to the separation of c-Jun and c-Fos dimers, causing the downregulated transcription of DAB2. In conclusion, topical hyperthermia treatment can inhibit the transcription of DAB2 gene, promote macrophage M1 polarization, and promote the treatment of sporotrichosis via AP-1 complex.

Demystification of the effects of docosahexaenoic acid on the PPAR signaling pathway in psoriasis S Morin 2,1 , M Simard 2,1 and R Pouliot 2,1 1 Pharmacy, Universite Laval, Quebec, Quebec, Canada and 2 CHU de Quebec-Universite Laval, Quebec, Quebec, Canada Psoriasis is a multifactorial skin disease that is distinguished histologically by the hyperproliferation of keratinocytes. n-3 polyunsaturated fatty acids (n-3 PUFAs), particularly docosahexaenoic acid (DHA), are known to have numerous anti-inflammatory effects in several pathologies, including psoriasis. The beneficial actions of DHA in psoriasis are primarily mediated by its interactions with the receptors activated via peroxisome proliferators (PPARs), as well as by its secretion of active anti-inflammatory metabolites. The aim of this study was therefore to assess the influence of DHA on the main characteristics of psoriasis, namely hyperproliferation and abnormal cell differentiation of lesional keratinocytes, through the PPAR signaling pathway, using a tissue-engineered psoriatic model. Psoriatic skin substitutes were produced according to the self-assembly method, using culture medium supplemented with 10 mM DHA in comparison with regular medium. Three different psoriatic cell populations were used. The supplementation of the culture media with DHA regulated the expression of cell differentiation proteins in psoriatic substitutes. Moreover, the added DHA was correctly incorporated into the membrane phospholipids of the epidermis and metabolized into eicosapentenoic acid (EPA) in psoriatic substitutes supplemented with DHA. Also, the addition of DHA to the culture medium decreased the synthesis of lipid mediators derived from n-6 PUFAs, known to be overexpressed in psoriasis. Finally, DHA supplementation positively restored the expression of PPAR receptors, which is deregulated in the pathology and causes a decrease in the synthesis of TNF-a. Ultimately, our results show that DHA has beneficial effects in attenuating the psoriatic features which are achieved through the signaling pathway of PPARs.

Systemic hyperinflammation as a driver of maculopapular drug exanthema in severely ill COVID-19 patients? Y Mitamura 1 , D Schulz 2 , I Kolm 3,4 , S Oro 5 , M Levesque 3,4 , E Maverakis 6 , C Akdis 1 and M Brü ggen 3,4 1 Swiss Institute for Allergy Research (SIAF), Davos, Switzerland, 2 Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland, 3 UniversitatsSpital Zurich, Zurich, Switzerland, 4 University Zurich, Faculty of Medicine, Zurich, Switzerland, 5 Henri Mondor Hospital, Paris, France and 6 University of California, Davis, Sacramento, California, United States Coronavirus disease 2019 (COVID-19) has been associated with cutaneous findings, some being the result of drug hypersensitivity reactions. Here, we utilize imaging mass cytometry (IMC) to characterize the cutaneous immune response in maculopapular drug rashes (MDR), including those associated with COVID-19 infection (COVID MDR). For comparison, skin from healthy controls and patients with drug rash with eosinophilia and systemic symptoms (DRESS) was analyzed. Results demonstrated that COVID MDR are characterized by a more prominent infiltration of cytotoxic CD8 + T cells and highly activated, phenotypically shifted monocyte/macrophage (Mo/Mac) clusters in comparison to MDR and DRESS. RNA sequencing transcriptome of the affected skin also demonstrated a more robust cytotoxic response in lesional COVID MDR skin. Serum proteomic profiling of COVID MDR patients revealed up-regulation of various inflammatory mediators (IL-4, IL-5, IL-8, IL-18, IL-6, TNF, and IFN-g), eosinophil and Mo/Mac -attracting chemokines MCP-2, MCP-3, MCP-4 and CCL11. Analyses of cytokine networks demonstrated a relatively milder cytokine storm in DRESS compared to COVID MDR, while MDR did not exhibit such features. These results suggest that a massive systemic cytokine storm promotes activation of Mo/Mac and cytotoxic CD8 + T cells, which impacts MDR development in severely ill COVID-19 patients.

1,2,5 and C Park 1,2,5 1 Department of Dermatology and Cutaneous Biology Research Institute, Yonsei University College of Medicine

United States Atopic March (AM) represents a typical progression of allergic diseases that often begin early in life, which has a role for the strongest evidence for systemic involvement of atopic dermatitis (AD). However, the mechanism underlying the development of AM in patients with AD is still unknown. To elucidate the possible mechanisms which might be engaged in AM, whole-transcriptome analysis was done with the skin biopsy specimens, blood samples in AD, AM, and healthy controls. Metabolic pathways-related genes were one of the most enriched in AM samples compared with AD and healthy controls

Knock-down of FABP5 in T cells inhibited IL-17A expression. Direct correlation was observed between FABP5 expression and IL-17A level. Taken together, the results indicate that 'fatty acid binding protein 5' might be as a possible biomarker to explain the progression of atopic march