bluuebunny/crossref_metadata_2025_split huggingface dataset:
c-Kit inhibitors prevent respiratory viral infection-induced acute asthma via the blockade of innate lymphoid cell activation
Authors: Chang Ya-Jen , Lai Alan Chuan-Ying , Wu Han-Chih , Umetsu Dale 
Published: January 2023

Abstract
Asthma is a major public health problem that affects nearly 10% of the general population and is thought to be mediated by allergen-specific Th2 cells, adaptive immunity and allergic inflammation. Current treatments for asthma generally focus on minimizing the Th2-driven eosinophilic inflammation with the use of anti-inflammatory therapies such as corticosteroids. However, this approach, targeting the adaptive Th2 cell immunity with corticosteroids, has not reduced the high rates of hospitalizations for acute asthma, most often caused by acute viral infection, including influenza. Recently, type 2 innate lymphoid cells (ILC2) expressing c-Kit have been shown to expand during influenza infection and directly caused airway hyper reactivity (AHR), a cardinal feature of asthma. We now show that the treatment of influenza-infected mice with c-Kit kinase inhibitors blocked the development of AHR and airway inflammation and greatly reduced the number and function of ILC2 cells, whereas the treatment with corticosteroids, commonly used to treat acute asthma, failed to prevent the influenza-induced AHR. We also demonstrated that c-Kit function is required for normal ILC2 cell function and for influenza-induced AHR, and that c-Kit kinase inhibitor inhibits murine lung ILC2 cell proliferation and cytokine productions in vitro and in vivo. Furthermore, the treatment of c-Kit inhibitor did not affect in vivo viral clearance. Our study demonstrated the crucial role of c-Kit in modulating the ILC2 activation in the lungs, particularly in respiratory viral infection induced acute asthma.
Imbalance of Peripheral CD4+T Cell Subsets in Active Vitiligo
Authors: Zhen Yu , Li Shanshan 
Published: January 2023

Abstract
Accumulating studies have indicated that vitiligo is one kind of autoimmune diseases and CD4+T cells play important roles in the pathogenesis of vitiligo. However, there have been very limited papers concerning the profile of circulating CD4+T cell subsets in active vitiligo. To clarify this issue, we investigated the changes of peripheral Th1, Th2, Th17, Tfh and Tregs from 30 patients with active vitiligo. We found that compared with healthy controls, the percentages of circulating Th1 and Th17 were significantly increased, while the proportions of Th2 and Tregs showed no significant difference to healthy controls. Similar results were got in qualification of their corresponding transcription factors at mRNA level. In addition, the percentage of CD4+CXCR5+Tfh was significantly elevated in vitiligo patients. Compared with healthy controls, the expression level of IL-17A was significantly increased in sera of patients with active vitiligo, while the productions of IFN-γ, IL-4, TGF-β had no significant change. The imbalance observed between the effector and suppressor CD4+T cells in the current study suggests their involvement in the pathogenesis of vitiligo. Besides these changes of cellular immunity, increased Tfh indicates humoral immunity may also be responsible for development of vitiligo.
Autoimmune T cells binds to self antigen weakly in the thymus but greatly upregulate the binding strength in the periphery
Authors: Liu Baoyu , Blanchfield J. Lori , Zhu Cheng , Evavold Brian D. 
Published: January 2023

Abstract
How autoimmune TCRs progress through thymocyte selection to egress in the periphery and induce disease is unclear. Autoimmune TCRs are believed to be of low affinity for self antigens due to the process of thymocyte negative selection. Using an experimental autoimmune encephalomyelitis (EAE) mouse model, we have cloned two tetramer positive myelin oligodendrocyte glycoprotein (MOG)35-55-specific TCRs (named B8 and 1C9) from polyclonal CD4+ T cells; both TCRs have a high two dimensional (2D) affinity for MOG (similar to a pathogen-specific TCR SMARTA for an LCMV epitope gp66-77) by the micropipette adhesion frequency assay. A second critical feature of antigen recognition is the bond lifetime between the TCR and pMHC that occurs under applied force. To this end, we have produced retrogenic mice for the two TCRs and used their thymocytes on biomembrane force probe (BFP) to measure single TCR-pMHC bond lifetimes. Despite their high affinity, both TCRs had short bond lifetimes with the MOG antigen displaying a slip bond where bond lifetimes decrease with increasing force. In contrast, the same TCRs on naïve T cells in the periphery displayed much longer bond lifetimes (up to 100 fold) and strong catch bonds (a counterintuitive type of molecular bond that strengthens under force), suggesting physiological regulation of TCR kinetics within single T cell clones. In comparison, the SMARTA TCR formed indistinguishable catch bonds with gp66-77 on thymocytes and naïve T cells. Therefore, these data identify bond lifetime under force as a unique kinetic property of autoimmune TCRs where weak interactions in the thymus potentially avoid negative selection yet in the periphery the TCRs bind with sufficiently long lifetime to promote autoimmunity.
Vitamin D increases the human endosomal TLR response against Mycobacterium tuberculosis nucleic acids
Authors: Cervantes Jorge L. , Oak Esther , Garcia John , Salazar Juan C. 
Published: January 2023

Abstract
Mycobacterium tuberculosis (Mtb) infects macrophages where it avoids elimination by interfering with host defense mechanisms. Type I IFNs are produced by activation of endosomal TLRs after recognition of nucleic acids. TLR importance is underlined by the fact that the TLR-adaptor molecule MyD88 pathway in macrophages is important in confining Mtb within phagolysosomes, mycobacterial clearance, and an adequate innate and adaptive immune response against Mtb. Vitamin D (VD) has a positive effect in macrophage activation, phagocytosis, restriction of Mtb growth, and killing of the mycobacteria.
We aimed to characterize the endosomal TLR-signaling of human macrophages, as they are appear crucial in determining the fate of the disease, and explore if variations in Type I IFN responses correlate with differences in Mtb nucleic acids derived from different Mtb genotypes. Stimulation with DNA from Mtb of different lineages elicited differential NF-κB and IRF inflammatory responses in THP-1 derived macrophages. We also studied the effect of VD on these responses, as it is known to activate macrophages and enhance their antimycobacterial activity. Pretreatment with VD increased the response to DNA from HN878 and virulent strain H37Rv. It also enhanced the response to RNA from M. smegmatis and attenuated M. bovis strain BCG.
No previous study has evaluated Type I or Type II IFNs response differences between different Mtb strains. This is of great importance as type I IFNs appear to strongly inhibit macrophages responsiveness to IFN-γ, and are associated with active TB. Understanding VD-mediated activation occurring at the pulmonary alveoli will impact the design of novel therapeutic and successful immunization strategies.
Extracellular High mobility group box 1-induced epithelial mesenchymal transition through β-catenin pathway in human airway epithelial cells
Authors: Lee Chen-Chen , Chen Yu-Ching , Wu Reen , Wang Chien-Neng 
Published: January 2023

Abstract
High mobility group box 1 (HMGB1) protein belongs to late inflammatory phase cytokine which shows a crucial role in the pathology of chronic pulmonary inflammatory diseases. Epithelial–mesenchymal transition (EMT) is implicated in airway remodeling and lung dysfunction in chronic inflammatory airway diseases. At present, the effects and mechanisms of HMGB1 in EMT of human airway epithelial cells is still unclear. In this study, we found that HMGB1 treatment modulated EMT-related gene expression in human primary airway epithelial cells by RNA sequencing assay. HMGB1 induced downregulation of E-cadherin and ZO-1, and upregulation of vimentin mRNA transcription and protein translation in a dose-dependent manner. To dissect the mechanisms of HMGB1-induced EMT in human airway epithelial cells, we used western blotting, RNA interference and chemical inhibitors to investigate. Treatment with PI3K inhibitor (LY294006) and β-catenin shRNA reversed HMGB1-induced EMT. HMGB1 caused AKT phosphorylation, resulting in GSK3β inactivation, cytoplasmic accumulation, and nuclear translocation of β-catenin to induce EMT in human airway epithelial cells. Additionally, HMGB1 upregulated expression of receptor for advanced glycation products (RAGE), but not that of Toll-like receptor (TLR) 2 or TLR4, and RAGE shRNA attenuated HMGB1-induced EMT in human airway epithelial cells. In conclusion, we found that extracellular HMGB1 induced EMT through RAGE and β-catenin signaling pathway which might deteriorate bronchial epithelium which enhance disease severity and steroid resistance of airway.
HDAC inhibitors enhance CD1d-dependent NKT cell responses to lymphoma
Authors: Tiper Irina V , Webb Tonya J 
Published: January 2023

Abstract
Histone deacetylases (HDACs) influence expression of genes implicated in tumor initiation, progression and anti-tumor responses. We hypothesize that tumors use epigenetic mechanisms to dysregulate CD1d-mediated antigen processing and presentation, which leads to a functional impairment in the ability of Natural killer T (NKT) cells to recognize and destroy cancerous cells. In this study, we treated CD1d-expressing tumor cells with HDAC inhibitors (HDACi) to assess CD1d-dependent NKT cell responses to B cell lymphoma. Consistent with previous studies, we found that treatment with Trichostatin A, a pan-HDACi, enhanced both CD1d and MHC class II-mediated antigen presentation. Similarly, treatment of B cell lymphomas with other HDACi, Panobinostat and Vorinostat, resulted in enhanced CD1d-dependent NKT cell responses. Mechanistically, we found that HDAC2 binds to the CD1d promoter and knockdown of HDAC2 in tumor cells enhanced their immunogenicity. The observed changes are due at least in part to a dose-dependent increase in both CD1d mRNA and CD1d cell surface expression. In addition, treatment with HDCAi resulted in a decrease in inflammatory cytokine secretion by B cell lymphomas. To examine the therapeutic potential of HDACi, we treated human peripheral blood mononuclear cells with TSA and Panobinostat. Treatment with these HDACi did not suppress T cell activation; conversely, treatment with a novel HDAC4 inhibitor MC1568 suppressed T cell responses. Taken together, our studies demonstrate the efficacy of HDACi in restoring anti-tumor responses to B cell lymphomas through both cell-intrinsic and extrinsic factors and strongly implicate a role for select HDACi in cancer immunotherapeutic strategies.
NF-κB and MAPK signaling pathways regulate the IL6 mRNA stability under TLR4 by regulating the expression and degradation of Arid5a
Authors: Nyati Kishan K , Masuda Kazuya , Dubey Praveen , Zaman Mohammad Mahabub-Uz , Kishimoto Tadamitsu 
Published: January 2023

Abstract
AT-rich interactive domain (ARID) 5a controls the IL-6 mRNA stability by binding to its 3′UTR region and preventing it from degradation by Regnase-1. This mechanism was shown to contribute to the elevation of IL-6 levels, which causes the development of autoimmune diseases. However, almost nothing is known about the regulatory mechanisms of Arid5a mRNA and protein expression. In the present study, we have investigated the regulatory mechanisms of Arid5a at transcriptional, post-transcriptional and post-translational levels under TLR4 signaling. We found that in response to LPS stimulation NF-κB binds to the promoter region of Arid5a and induce its gene expression. After expression of Arid5a mRNA, MKP-1 signaling induces AUF-1 to translocate from the nucleus to the cytoplasm where it binds to the 3′UTR region of Arid5a and resulting in its destabilization. Inhibition of MKP-1 and AUF-1 results in the stabilization of Arid5a mRNA, which leads to higher expression of IL6, suggesting that this pathway has a significant role in regulating IL6 mRNA through Arid5a. We also show that during the late phase of LPS stimulation, p38 MAPK phosphorylates the Arid5a protein at Ser 253, 433 and 458 positions that lead to its ubiquitination at lysine 80 and 93 positions resulting in degradation. Inhibition of Arid5a phosphorylation and degradation causes the over-production IL6 mRNA further supports the importance of Arid5a in the regulation of IL6. Our data demonstrate that LPS signaling controls IL6 mRNA stability; therefore, its regulation through up-regulation of Arid5a by NF-κB at the early phase, and down-regulation of Arid5a at the mRNA and protein level by MKP-1-mediated AUF1 and P38 MAPK signaling, respectively at the later phase.
Controls of MDA5 Activation by The 14-3-3 Protein Family
Authors: Liu Helene Minyi , Lin Chih-Pu 
Published: January 2023

Abstract
During RNA virus infection, RIG-I like receptors (RLRs), such as Retinoic acid-inducible gene I (RIG-I) and Melanoma differentiation-associated protein 5 (MDA5), recognize cytoplasmic viral RNA and activate downstream adaptor proteins to produce type I interferon (IFN). RIG-I is known to bind short dsRNA (&lt;200 bp) whereas MDA5 prefers to bind to dsRNA which are longer than 2000 bp. It has been reported that RIG-I can interact with TRIM25, which is the ubiquitin E3 ligase of RIG-I during viral infections, and with the chaperon protein 14-3-3ɛ, which facilitate RIG-I translocate to mitochondria. However, the molecular mechanisms of MDA5 activation remain unclear. Here we show that certain 14-3-3 isoforms are crucial for MDA5-dependent type I IFN induction. Transfection of dsRNAs in different lengths to Huh7 RIG-I knocked-down cells reveals that MDA5 may specifically binds to long dsRNA and activate IFNβ promoter activity 3 hours post-RNA transfection. Also, overexpression of full-length MDA5 or the N-terminal CARD domains may constitutively activate IFNβ promoter activity, while C-MDA5 lacking both CARD did not show any ability to signal itself. We then applied dsRNA transfection or MDA5 overexpression to assess which 14-3-3 isoform is critical for MDA5 activation. We found that certain 14-3-3 isoform may bind to full-length MDA5 and N-MDA5 shown by co-immunoprecipitation, and ectopic expression of 14-3-3 may enhance MDA5-dependent activation of IFNβ promoter. Further studies of the molecular mechanisms how 14-3-3 proteins participate and regulate in the MDA5-dependent signaling pathway will be investigated in order to define the critical steps of MDA5 activation during RNA virus infections.
Eosinophil migration is regulated by the transcription factor Aiolos
Authors: Bouffi Carine , Schollaert Kaila L , Morris David W , Fulkerson Patricia C 
Published: January 2023

Abstract
Accumulation of an abnormally high number of eosinophils (Eos) in tissues often results in damage and organ dysfunction in allergic disease. Preclinical and clinical studies have established that CCR3 ligands (CCL11, CCL24, CCL26) are critical for disease-associated tissue eosinophilia. Yet, blockade of the individual mediators (e.g. CCR3, CCL11) has been insufficient to completely resolve tissue eosinophilia, likely due to simultaneous local expression of multiple Eos-attracting mediators acting in parallel. Thus, delineating the molecular mechanisms that control Eos trafficking into tissues is clinically significant. We recently reported that the transcription factor Aiolos is expressed in murine Eos progenitors (EoPs) as well as mature Eos in mice and humans. We now show that the migratory response of Aiolos-deficient (AiolosKO) Eos is markedly impaired toward CCR3 ligands in vitro and in vivo, along with significantly reduced mRNA and surface expression of CCR3. Notably, migration of AiolosKO Eos toward leukotriene B4 is significantly reduced, suggesting that Aiolos-deficiency results in a global migratory defect. We also demonstrate a profound reduction in Eos accumulation in the small intestine of AiolosKO mice. These latter findings provide in vivo relevance to our findings as intestinal eosinophilia is CCL11 and CCR3 dependent. We further show that migration of adoptively transferred AiolosKO Eos into the airway of allergen-challenged mice was significantly reduced when compared to wild-type Eos in an experimental model of asthma, highlighting an intrinsic defect in tissue trafficking in the AiolosKO Eos. Collectively, our studies implicate Aiolos as a global regulator for eosinophil migration.
Global analyses of monocyte subsets revealed age-related alternations after stimulation of pathogen recognition receptors
Authors: Metcalf Talibah , Wilkinson Peter , Wertheimer Anne , Nikolich-Zugich Janko , Haddad Elias 
Published: January 2023

Abstract
In the aging population, intricate interactions between the innate and adaptive immune response is not as effective compared to younger adults. Monocytes play an important role in defense against microbes and express an array of pattern recognition receptors (PRRs). We applied a comprehensive approach to evaluate the effects of a broad range of innate immune agonists (LPS, CLO97, and 5′pppRNA) on monocyte subsets isolated from healthy non-frail adults and old subjects. We analyzed transcriptome data and measured cytokine and chemokine, ROS, and NO production. Under ex vivo conditions, we observed a larger proportion of genes were specifically upregulated in the classical (CD14+CD16−) and non-classical (CD14dimCD16+) monocytes while the intermediate (CD14+CD16+) monocytes showed a smaller proportion of upregulated genes. Distinct genes observed across both age groups for CD16+ monocytes included: CX3CR1, IL21R, IFITM1/2/3, SIGLEC10, and SOD1; whereas CD16− monocytes expressed CCR1/2, SELL, CD64, CD93, CD36, and CD14. Analysis of the transcriptional profiles elicited by innate agonists revealed age-related alternations in functional pathways. After stimulation of RIGI with 5′pppRNA, we observed that classical monocytes isolated from adults uniquely expressed the RIGI MDA5 mediated induction of IFNα and IFNβ pathway, as well as the IFNα transcript, which corresponded to higher levels of IFNα production. In addition, agonists elicited higher levels of IFNγ from non-classical monocytes isolated from adults. Our findings represent a comprehensive analysis of the influence of human aging on PRRs signaling and have implications for strategies to enhance the immune response in the context of infection or immunization.
Minocycline promotes the generation of dendritic cells with regulatory properties
Authors: Lee Chong-Kil , Kim Narae , Im Sun-A , Lee Jae-Hee , Park Chan-Su , Song Sukgil 
Published: January 2023

Abstract
Minocycline, which has long been used as a broad-spectrum antibiotic, also exhibits non-antibiotic properties such as inhibition of inflammation and angiogenesis. In this study, we show that minocycline significantly enhances the generation of dendritic cells (DCs) from mouse (BM) cells when used together with GM-CSF and IL-4. DCs generated from BM cells in the presence of minocycline (Mino-DCs) demonstrate the characteristics of regulatory DCs. Compared with control DCs, Mino-DCs are resistant to subsequent maturation stimuli, impaired in MHC class II-restricted exogenous Ag presentation, and show decreased cytokine secretion and allogeneic T cell stimulation in vitro. Mino-DCs also have a decreased ability to prime alloantigen-specific T cells when transferred to allogeneic mice. Splenic Mino-DCs generated in mice by injecting minocycline together with GM-CSF are also severely impaired in priming alloantigen-specific T cells in allogeneic mice. In allogeneic mice, Mino-DCs induce expansion of CD4+CD25+Foxp3+ T regulatory cells. Our study identifies minocycline as a new pharmacological agent that could be potentially used to increase the production of regulatory DCs for cell therapy to treat autoimmune disorders, allergy, and transplant rejection.
Inhalation injury causes recruitment of IL-12lo neutrophils late after injury
Authors: Kartchner Laurel B , Dunn Julia L , Stepp Wesley H , Vaughan Rachel , Glenn Lindsey I , Maile Robert , Cairns Bruce A 
Published: January 2023

Abstract
Inhalation injury causes increased morbidity and a 20% increase in mortality following burn injury. Although it is known that inhalation injury causes immune dysfunction among patients, few animal models of inhalation injury examine changes in the immune profile following inhalation injury. Our lab generated a clinically relevant murine model using female C57BL/6 mice (8–12 weeks, &gt;18g) that were intubated and subjected to a woodsmoke inhalation injury. Additionally, a subset of mice were subjected to a combined injury consisting of inhalation and burn injury (20% total body surface area). Increased mortality was only observed following combined injury (50% mortality within 5 days of injury, p&lt;0.05). Inhalation injury alone caused significant weight loss, peaking at 14 days post injury (p&lt;0.05). Bronchioalveolar lavage (BAL) performed 16 days post injury demonstrated increased cell recruitment following inhalation injury (1.5 fold, p=0.15) and combined injury (2.4 fold, p&lt;0.05) compared to sham controls. Cells recruited to the airway were identified as neutrophils and macrophages by flow cytometry. Intracellular staining demonstrated that neutrophils, but not macrophages, exhibited decreased expression of IL-10 and IL-12 following inhalation or combined injury. In our model, inhalation injury and combined injury cause cellular recruitment to the lungs and decreased production of cytokines known to be important for immune function. Thus we propose to use this model as a means to determine if changes to neutrophil activity contribute to increased susceptibility to bacterial infections and poor outcomes following inhalation or combined injury.
Cynomolgus macaque neutrophils express IL-4 and IL-10 in response to Mycobacterium tuberculosis bacilli
Authors: Mattila Joshua T , Flynn JoAnne L 
Published: January 2023

Abstract
Neutrophils are associated with increased disease severity in tuberculosis (TB) but mechanisms underlying their contribution to pathology are poorly understood. In granulomas, neutrophils localize to regions that are adjacent to macrophages, and we hypothesize that neutrophil-expressed cytokines can modify anti-mycobacterial immune responses. To investigate this, we examined pro- and anti-inflammatory cytokine production by neutrophils in Mycobacterium tuberculosis (Mtb) infected macaques, a nonhuman primate that replicates human TB. We found that intact bacteria were potent inducers of anti-inflammatory cytokine expression and viable Mtb elicited IL-10 while dead Mtb induced IL-4 expression. Bacterial stimulation and mycobacterial culture filtrate protein (CFP) induced TNF in peripheral blood neutrophils. Cytokine expression was not induced by stimulation with anti-CD3 antibody, poly I:C, or purified Mtb peptides and was independent of host infection status, suggesting this is an intrinsic property of neutrophils driven by mycobacterial TLR2/4 ligands. There was little polyfunctionality in neutrophils and most cells expressed either IL-4 or IL-10, or these cytokines in combination with TNF. Neutrophils were less efficient than T cells at cytokine production and expressed less cytokine on a per cell basis. Although there are more T cells than neutrophils in granulomas, we found similar frequencies of IL-4 or IL-10 expressing T cells and neutrophils, and identified IL-10+ neutrophils in caseum adjacent to epithelioid macrophages, a region associated with extracellular Mtb. These results suggest neutrophils are underappreciated sources of immunosuppressive cytokines that contribute to poor outcomes in TB.