bluuebunny/crossref_metadata_2025_split huggingface dataset:
TWEAK/Fn14 activation contributes to the pathogenesis of bullous pemphigoid
Authors: Liu Yale , Peng Lingling , Li Liang , Liu Chengfei , Hu Xiao , Xiao Shengxiang , Xia Yumin 
Published: January 2023

Abstract

Background
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) participates in various cellular effects by engaging its receptor of Fn14. Increased levels of soluble TWEAK are associated with systemic autoimmunity in patients with lupus erythematosus, rheumatoid arthritis or dermatomyositis. However, the role of TWEAK in bullous pemphigoid (BP) remains unknown.

Objectives
To explore the potential role of TWEAK/Fn14 activation in the pathogenesis of BP.

Methods
Twenty-three patients with BP and twenty healthy donors were recruited. The levels of TWEAK were determined in sera and BP fluids. Immunohistochemistry was performed with skin tissues for the expression of TWEAK, Fn14, and BP180. HaCaT cells were cultured in vitro, and received TWEAK stimulation. Some cells were pretreated with siRNA transfection or specific inhibitors before such stimuli.

Results
Serum levels of TWEAK increased in sera from BP patients, and correlated positively with anti-BP180 IgG. By immunohistochemistry, both TWEAK and Fn14 were overexpressed in BP lesion. In vitro experiments showed that TWEAK stimuli reduced BP180 expression in HaCaT cells and inhibited adhesion of cells to the culture dish. Consistently, the transfection of Fn14 siRNA preserved BP180 and protected cells from losing adherence. Moreover, specific inhibitors of the ERK and NF-κB pathways partially abrogated effect of TWEAK on cells. Finally, By silencing ADAM17 with siRNA, we found that ADAM17 mediated TWEAK-induced BP180 suppression.

Conclusion
TWEAK contributes to the pathogenesis of BP by reducing BP180 expression and cellular adherence, involving the activation of ERK and NF-κB pathways. TWEAK may serve as a biomarker or therapeutic target of BP.
Immune cell phenotype and function in different compartments of the gut-liver-axis in chronic liver disease
Authors: Bolte Fabian J , O’Keefe Ashley C. , Etzion Ohad , Ali Rabab , Serti Elisavet , Liang Jake , Heller Theo , Rehermann Barbara 
Published: January 2023

Abstract

BACKGROUND
The liver is exposed to gut-derived products via the portal vein and bacterial translocation is associated with chronic liver disease. Here we analyzed immune cell activation and function in three compartments of the gut-liver axis: systemic blood, portal vein blood and liver.

METHODS
Natural killer (NK) cells, mucosal associated invariant T (MAIT) cells and conventional CD8 T cells were studied in liver and blood of 29 patients with chronic hepatitis C prior to and after Sofosbuvir/Velpatasvir-induced viral clearance.

RESULTS
NK, MAIT and conventional CD8 T cells were more activated (CD69+, HLA-DR+) and more cytotoxic (CD107a+) in the liver than in systemic and portal blood. Monocytes were also more activated in the liver and plasma levels of monocyte-derived IL-18 correlated with liver inflammation. Consistent with the activation of intrahepatic immune cells, levels of sCD14, sCD163 and sCD27 were higher in systemic than in portal plasma. However, immune cell activation and degranulation were not different in systemic and portal vein blood. Likewise, the in vitro functional responses of monocytes to lipopolysaccharide and of MAIT cells to riboflavin-synthesizing bacteria did not differ between systemic and portal blood. Intrahepatic immune cell activation declined rapidly within four weeks of antiviral therapy and remained stable for up to 36 weeks post treatment.

CONCLUSIONS
Immune cell activation and inflammation are compartmentalized to the liver in patients with compensated HCV-related liver disease. Plasma markers of immune cell activation are higher in systemic than in portal plasma. The rapid decline of intrahepatic immune cell activation suggests that it is primarily driven by viral infection.
A Regulatory Role for “MFehi” Macrophages In Adipose Tissue Iron Homeostasis
Authors: Hubler Merla , Hasty Alyssa , Moestrup Soren , Etzerodt Anders 
Published: January 2023

Abstract
Macrophages are the predominant immune cell in adipose tissue (AT) and exhibit phenotypic variability depending on the obesity state of the tissue. Lean AT contains a population of anti-inflammatory “M2” AT macrophages (ATMs), whereas, obesity is associated with an influx of inflammatory “M1” ATMs. The role of M2 ATMs in maintenance of a healthy lean state is relatively undefined. Our lab has previously published the discovery of the “MFehi” population of M2 ATMs, which has a two-fold increase in intracellular iron content and exhibits increased expression of genes involved in iron uptake (e.g. CD163), storage and release. This population composes 25% of M2 ATMs and exists in both lean and obese mouse and human AT. It remains unknown whether MFehi contribute to AT iron metabolism. To better understand how MFehi are regulating iron in AT, we provided iron through diet and by IP injection and predicted that MFehi compensate for excess iron to protect adipocytes from iron overload. We found that only MFehi take up the iron, and their gene expression corresponds with this uptake. Furthermore, there is no change in iron content or gene expression in adipocytes. Even though the MFehi change their gene expression in obese AT, we still observed that they are able to compensate for excess iron in the tissue. To determine the impact of MFehi on the systemic metabolic state, we depleted M2 ATMs in mice with cytotoxic CD163-targeted liposomes. Our preliminary studies have revealed CD163-targeted liposomes as a novel technique to target CD163-expressing M2 ATMs. These studies will allow us to characterize the role of the MFehi population in maintaining healthy adipocyte iron concentrations and, thereby, insulin sensitivity.
Selective oral ROCK2 inhibitor reduces clinical scores in patients with Psoriasis Vulgaris and normalizes skin pathology via concurrent regulation of IL-17 and IL-10 levels
Authors: Zanin-Zhorov Alexandra , Weiss Jonathan M , Trzeciak Alyssa , Chen Wei , Zhang Jingya , Nyuydzefe Melanie , Arencibia Carmen , Polimera Seetharam , Fuentes-Duculan Judilyn , Bonifacio Kathleen , Kunjravia Norma , Cueto Inna , Berger Mark , Krueger James , Ryan John L , Waksal Samuel D 
Published: January 2023

Abstract
Targeted inhibition of Rho-associated kinase 2 (ROCK2) down-regulates pro-inflammatory T-cell response, while increasing the regulatory arm of immune response in animals models of autoimmunity and T helper 17 (Th17)-skewing human cell culture in vitro. We conducted a Phase 2, open-label, dose-finding study to evaluate the safety, tolerability, and activity of selective ROCK2 inhibitor, KD025, in subjects with Psoriasis Vulgaris who failed first-line therapy (NCT02317627 at ClinicalTrials.gov). Here, we report that oral administration of KD025 reduces Psoriasis Area and Severity Index (PASI) scores in 85% of patients completing the study, with minimal side effects. In the 400 mg QD and 200 mg BID cohorts 42% and 71% of patients respectively achieved at least a 50% decrease in PASI score (PASI 50) after three month of treatment. KD025 treatment reduced levels of both IL-17 and IL-23, but no IL-6 and TNF-a in the peripheral blood of clinical responders, whereas IL-10 levels were increased at the end of the study. The clinical improvement and changes in cytokine levels were associated with decreased epidermal thickness, T-cell infiltration and down-regulation of key molecules implicated in the regulation of the Th17 pathway, such as ROCK2, pSTAT3, RORgt and IRF4 in the skin. Collectively, these data demonstrate that orally available selective ROCK2 inhibitor down-regulates Th17-driven autoimmune response and improved clinical symptoms in psoriatic patients via defined molecular mechanism that involves concurrent modulation of cytokines without deleterious impact on the rest of the immune system.
Interplay between keratinocyte STAT1 and STAT3 signaling controls skin inflammation and T-cell development in a mouse model of psoriasis
Authors: Archer Nate , Lee Steven K , Ortines Roger V , Wang Yu , Liu Haiyun , Miller Robert J , Dillen Carly A , Marchitto Mark , Ashbaugh Alyssa G , Uppal Angad , Cai Sarah , Miller Lloyd S 
Published: January 2023

Abstract
Psoriasis is an autoimmune skin disease affecting 2–3% of the population that is driven by IL-17 responses. Although STAT3 promotes the development of IL-17-producing T cells, STAT3 overexpression in keratinocytes is sufficient to induce psoriasiform dermatitis in mice. To study the role of STAT3 in keratinocytes versus T cells in psoriasis, the imiquimod mouse model of psoriasiform dermatitis was performed on mice with specific deletion of STAT3 in either keratinocytes (K5-creERT2×STAT3fl/fl [K5-STAT3]) or T-cells (Lck-cre×STAT3fl/fl [Lck-STAT3]). Unexpectedly, K5-STAT3 mice but not Lck-STAT3 mice had reduced skin inflammation and inflammatory cell influx compared to wt mice, suggesting that STAT3 signaling in keratinocytes rather than T cells was more important determinant for mediating the skin inflammation. K5-STAT3 mice also had increased IFN-γ+ T cells but less IL-17+ T-cells compared to wt mice, indicating that loss of STAT3 signaling in keratinocytes dampened inflammation by inhibiting IL-17 responses while promoting IFN-γ responses. Since interferon/STAT1 signaling responses can be inhibited by STAT3, we hypothesized that loss of STAT3 signaling in keratinocytes would lead to enhanced interferon/STAT1-signaling and responses. Consistent with this possibility, histologic sections from the inflamed skin of K5-STAT3 mice had increased epidermal STAT1 phosphorylation and increased mRNA expression of interferon-regulated chemokines CXCL10 and CXCL11 compared with wt mice. Taken together, these findings indicate that keratinocytes can regulate T cell responses in the skin and STAT3 signaling in keratinocytes could represent a therapeutic target in psoriasis.
Map3K14 signaling attenuates the development of colorectal cancer through activation of the non-canonical NF-κB signaling cascade
Authors: Allen Irving C , Eden Kristin , Heid Bettina , Holl Eda K 
Published: January 2023

Abstract
Dysregulation of NF-κB signaling is a common feature in Colorectal Cancer (CRC). While the canonical signaling pathway is well characterized, the non-canonical NF-κB signaling cascade is understudied. Thus, we evaluated the hypothesis that non-canonical NF-κB signaling significantly modulates CRC pathogenesis. To evaluate this hypothesis, we initially conducted a meta-analysis of human gene expression data. Using this approach, we found that non-canonical NF-κB signaling is significantly down-regulated in CRC patients and the extent of pathway attenuation is correlated with disease severity. These findings were confirmed in patient biopsy specimens, where we found significantly reduced expression of ligands, receptors, regulators, and chemokines associated with non-canonical NF-κB signaling. Notably, we observed significantly reduced CCL19, CCL21, CXCL12, and CXCL13 expression in CRC patients compared to healthy controls. To gain mechanistic insight, we utilized genetically modified mice lacking the kinase Map3K14 (NIK), which is essential for non-canonical NF-κB signaling. Nik−/− mice exhibited ablation of non-canonical NF-κB signaling and significantly increased epithelial cell proliferation in the GI tract compared to wild type mice in both in vivo and in vitro studies. Together, our data defines a protective role for non-canonical NF-κB signaling in the gut during CRC and identifies a highly protective role for Map3K14 in attenuating epithelial cell proliferation.
The innate immune receptor, NLRX1, functions as a tumor suppressor by reducing colon tumorigenesis and key tumor-promoting signals
Authors: Koblansky A Alicia , Truax Agnieszka D. , Liu Rongrong , Montgomery Stephanie A , Ding Shengli , Wilson Justin E , Brickey W June , Hu Peizhen , Li Zengshan , Lund Pauline Kay , Ting Jenny P.Y. 
Published: January 2023

Abstract
NLR (NOD-like receptor) proteins are intracellular innate immune sensors/receptors that regulate immunity. This work shows that NLRX1 serves as a tumor suppressor in colitis-associated cancer (CAC) and sporadic colon cancer by keeping key tumor promoting pathways in check. Nlrx1−/− mice were highly susceptible to CAC, showing increases in key cancer-promoting pathways including NF-kB, MAPK, STAT3 and IL-6. The tumor-suppressive function of NLRX1 originated primarily from the non-hematopoietic compartment. This prompted an analysis of NLRX1 function in the Apcmin/+genetic model of sporadic gastrointestinal cancer. NLRX1 attenuated Apcmin/+colon tumorigenesis, cellular proliferation, NF-kB, MAPK, STAT3 activation and IL-6 levels. Application of anti-IL6R antibody therapy reduced tumor burden, increased survival and reduced STAT3 activation in Nlrx1−/−Apcmin/+mice. As an important clinical correlate, human colon cancer samples expressed lower levels of NLRX1 than healthy controls in multiple patient cohorts. These data implicate anti-IL6R as a personalized therapeutics for colon cancers with reduced NLRX1.
Merkel Cell Carcinoma viral oncoprotein-specific polyclonal T cells can be generated from patients and from healthy donors
Authors: Davies Sarah I , Whitehill Gregory , Yu Quan , Chang Mark Jesse , Keyvanfar Keyvan , Brownell Isaac , Buck Christopher , Barrett John , Muranski Pawel 
Published: January 2023

Abstract
Truncated large T (LT-T) and small T (ST) antigens of Merkel Cell Polyomavirus (MCV) are viral oncoproteins critical for pathogenesis of Merkel Cell Carcinoma (MCC), making this malignancy an attractive target for immunotherapy. We explored feasibility of generating LT-T and ST specific T cells from 12 healthy donors and 4 patients with MCC. Manufactured overlapping peptide libraries (pepmixes) spanning entire LT-T and ST proteins were pulsed onto autologous dendritic cells or peripheral blood mononuclear cells and co-cultured with lymphocytes in presence of IL-2, IL-7 and IL-15. Analogous cultures were generated using BK and JC polyomavirus LT pepmixes and PRAME (MCC patients). On day 14, cells were tested for recognition of cognate pepmixes. T cells from 4/12 (33.3%) healthy donors released IFN-γ and/or TNFα (average 0.48 ± 0.144 %) in response to MCV T antigens, predominantly in CD4± cells. 2/4 patients with MCC had a robust T cell response against MCV LT (2.23 ± 0.65%), 3/4 patients responded to JCV LT (3.56 ± 1.92%), and 2/4 responded to PRAME (1.18 ± 0.707%). T cells specific for JC or BK LT antigens demonstrated mutual cross-reactivity, but negligible cross reactivity with MCV LT and vice versa, suggesting that the more abundant JC and BK-specific cells do not confer protection against MCC. Our data indicate that while MCC subjects have strong responses healthy donors harbor only rare memory T cells specific for MCC oncoproteins. Based on these findings we are developing highly-active clinical-grade MCC-specific T cells for adoptive immunotherapy.
Engineering adoptive T cell therapy for efficacy in ovarian cancer
Authors: Anderson Kristin G , Bates Breanna M. , Chiu Edison Y. , Greenberg Philip D. 
Published: January 2023

Abstract
Over 20,000 women are diagnosed with ovarian cancer annually; more than half will die within 5 years, which has changed little over the last 20 years. One promising new treatment strategy employs immune T cells engineered to target proteins uniquely overexpressed in tumors, with the potential to control tumor growth without toxicity to healthy tissues. Recently, mesothelin (MSLN) has been identified as a valid antigen target in ovarian cancer; minimally expressed in healthy cells, MSLN contributes to malignant and invasive phenotypes. In preclinical studies using patient-derived cell lines or the mouse ID8 ovarian tumor model, we found that T cells engineered to express a high-affinity MSLN-specific T cell receptor (TCR) can kill ovarian tumor cells in vitro. In vivo, adoptively transferred TCR-engineered T cells preferentially accumulate within disseminated ID8 tumors, delay tumor growth and prolong mouse survival, but our data also show the tumor microenvironment (TME) can limit engineered T cell persistence and function. Other analyses show human therapy will face similar TME-mediated obstacles. The ovarian cancer TME is a nutrient- and oxygen-deprived milieu, and adaptive metabolic responses by infiltrating T cells have protean effects on T cell function. Thus, strategies that modulate T cell metabolic pathways, and thereby influence activity in the TME, might enhance T cell function and improve anti-tumor efficacy by overcoming a critical component of immune evasion by solid tumors. Ongoing studies will be discussed that are exploring strategies to overcome elements common to the human and murine TME, including direct modulation of the environment and T cell engineering to promote T cell survival and function.
Dissection of CD8+ T cell immunodominance hierarchy in human influenza virus infection
Authors: Sant Sneha Ashok , Parra Sergio Quinones , Rossjohn Jamie , Gras Stephanie , Loh Liyen , Kedzierska Katherine 
Published: January 2023

Abstract
Based on magnitude, virus-specific CD8+ cytotoxic T lymphocyte (CTL) responses can be grouped as immunodominant and subdominant. Such immunodominance hierarchies are governed by multiple factors, including naïve T cell precursor frequency, proliferative capacity and clonotypic diversity of Ag-specific CTLs. However, how these factors determine together inter/intra-individual immunodominance remains elusive. In this study, we dissected CTL immunodominance hierarchy for universally conserved influenza (IAV)-specific epitopes. Our data from 59 donors covering the HLAI types presenting universally conserved IAV-specific peptides, HLA-A* 0201, A*0301, B*2705, B*5701, B*1801 and B*0801, revealed that CTLs directed against HLA-A* 0201:M158 were immunodominant, except in A*0201+B*2705+ heterozygous individuals, where the HLA-B* 2705-NP383 recalls higher magnitude CTL responses. Subsequently, we further dissected the basis of B*2705 immundomination over A*0201 by analyses of T cell Receptor (TCRαβ) repertoire, TCR avidity and kinetics of killing and proliferation. Our data show that following in vitro peptide stimulation, B*2705:NP383 CTLs proliferate rapidly acquiring higher levels of polyfunctionality than A*02:M158 specific CTLs. Furthermore, ex vivo single-cell paired CDR3αβ analysis revealed that public A*0201:M158 TCRs characterized by Vβ19/Vα27 profiles in A*0201 individuals are significantly reduced/absent in A*0201+B*2705+ individuals. Clonal analysis of M158 dominant public TCRs suggested B*2705-mediated removal of self-reactive TCRs and is under investigation. Our study provides insights into the importance of human IAV-specific immunodominance at quantitative and qualitative levels.
Skin homing and highly suppressive (CD45RA−CD27−) Tregs associated with ultraviolet radiation exposure
Authors: Hesterberg Rebecca , Akuffo Afua Adutwumwa , Hampras Shalaka S , Messina Jane L , Fenske Neil A , Cherpelis Basil , Schell Michael J , Reed Rhianna , Balliu Juliana , Rollison Dana E , Epling-Burnette Pearlie K 
Published: January 2023

Abstract
Immune suppression is a critical risk factor for the development of cancer. Understanding how carcinogens impact the immune system in immunocompetent individuals may give rise to relevant information about the biological processes that occur in precancerous lesions and how these contribute to cancer progression. UV radiation (UVR) is a known risk factor for keratinocyte cancer, but its association with immunosupperssive CD4+FoxP3+ regulatory T (Treg) cells is not established. To evaluate the association between UVR and Tregs, an epidemiological study (n=350) was conducted among a cohort undergoing skin cancer screening. Patients were recruited at the University of South Florida Dermatology clinic and UVR exposure was quantified by spectrophotometric readings from the axilla (sun-unexposed) and two sun exposed regions including the forehead and upper forearm. Populations of T cells were determined by flow cytometry using peripheral blood samples collected at the same clinic visit. Subsets of CD8+ T cell, CD4+ T cells, and total Treg numbers showed no significant correlation to UVR exposure. Interestingly, the proportion of Tregs that lacked expression of CD45RA and CD27 (ie, effector Tregs) were positively associated with UVR exposure (r=0.127, p=0.020 and r=0.197, p=0.0002, respectively). This population of Tregs has been shown to be more suppressive and expanded in a pre-leukemic patient population. Skin-associated CLA+ (r=0.167, p=0.002) and CCR4+ (r=0.19, p=0.0004) Tregs were also positively correlated with UVR exposure. These data demonstrate the association between UVR exposure and the expansion of immunosuppressive skin-associated Treg subsets that may contribute to the process of skin cancer progression.
Eradication of hepatocellular carcinoma by augmenting PD-L1 blockade efficacy with suppression of cell-cycle related kinase (CCRK)-induced myeloid-derived suppressor cells
Authors: Zhou Jingying , Liu Man , Sun Hangyong , Feng Yu , Wong John , Chan Anthony W.H. , Chow King-Lau , Chen Zhiwei , Cheng Alfred S.L. 
Published: January 2023

Abstract
Myeloid-derived suppressor cells (MDSCs) constitute to tumor immunosuppression and immune checkpoint blockade therapy resistance. We have recently reported the cell-autonomous pro-tumorigenic functions of cell cycle-related kinase (CCRK) in hepatocellular carcinoma (HCC), but its role in tumor immune evasion remains unknown. Here we report that the hepatoma-intrinsic CCRK signaling renders T-cell dysfunction by induction of MDSCs. CCRK stimulated immunosuppressive CD11b+CD33+HLA-DR−MDSC generation from human PBMCs through up-regulating interleukin-6 (IL-6). Mechanistically, CCRK activated nuclear factor-kappa B (NF-κB) in an enhancer of zeste homolog 2 (EZH2)-dependent manner and facilitated NF-κB-EZH2 co-binding to IL-6 promoter. In corroboration with the CCRK-inducible transgenic mouse model, we demonstrated that hepatic CCRK induced IL-6 to specifically expand and recruit polymorphonuclear-MDSCs with potent T-cell-inhibitory function to the liver. In contrast, genome-deletion of tumoral Ccrk expression or nanoparticle-mediated hepatic IL-6 inhibition increased cytotoxic IFN-γ+TNF-α+CD8+T-cell infiltration and impaired tumorigenicity, which was rescued by restoring polymorphonuclear-MDSCs. More importantly, Ccrk deletion significantly enhanced the efficacy of anti-PD-L1 therapy to eradicate large hepatoma in an intrahepatic model. As we also showed that CCRK positively correlated with the intra-tumoral CD11b+CD33+HLA-DR−MDSCs and poor survival rates of HCC patients, our results establish an immunosuppressive function of the hepatoma-intrinsic CCRK signaling and highlight a therapeutic target whose inhibition might potentiate cancer immunotherapy.