bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dysregulation of T follicular cells and antibody responses in high fat-diet associated lupus development in MRL/lpr mice
Authors: Zhang Xin , Meng Juan , Shi Xuhua , Patel Ronak , Ray Alicia , Hellmers Linh , Davis William , Zakem Jerald , Keshavamurthy Chandana , You Zongbing , Quinet Robert 
Published: January 2023

Abstract

Background/Purpose
Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by persistent inflammation, autoantibodies production, and organ damage. Genetic predisposition and environmental factors such as fat diet/obesity contribute to lupus pathogenesis. Here, we investigated the role of immune cells, especially T follicular helper (Tfh) cells and T regulatory (Treg) cells, in bridging obesity and SLE manifestations using lupus prone mice.

Methods
Fifty MRL/lpr mice were fed and grouped in a regular diet (RD) or high fat diet (HFD). Body weights and skin lesions were recorded weekly. Urine protein, serum IgG, anti-dsDNA antibody (Ab), and anti-nuclear Ab were detected. At week 14, kidney and skin biopsy were collected for H&E and PAS staining for histopathological lesions and quantified as kidney index and skin score. Immune cells in spleen were examined by flow cytometry and confirmed by slides staining.

Results
HFD induced a significant increase in body weight than RD (p&lt;0.01). SLE features, such as skin lesions, splenomegaly, proteinuria, higher kidney index, increase of anti-dsDNA Ab and IgG titer were observed in HFD mice. There were significant increase of germinal center B cells and plasma cells in the spleen of HFD mice. The percentage of Tfh cells and the ratio of Tfh/Treg were significantly increased in HFD group (p&lt;0.05).

Conclusion
HFD induced an exacerbated lupus development with dysregulated Tfh/Treg cells associated with increased of anti-dsDNA Ab in MRL/lpr mice, suggesting the central role of Tfh/Treg cells in linking HFD to autoimmunity in SLE. Intervention of healthy diet or restoring balance of Tfh/Treg cells may improve lupus symptoms and outcomes in genetically predisposed individual.
Supported by None
Nexinhib20 inhibits neutrophil adhesion and β2 integrin activation to prevent myocardial ischemia-reperfusion injury
Authors: Fan Zhichao , Liu Wei , Cronin Chunxia G , Wang Chengliang , Ruan Jianbin , Johnson Jennifer L , Catz Sergio , Sun Hao , Groisman Alex , Chen Yunfeng , Hu Liang , Vella Anthony T , Liang Bruce 
Published: January 2023

Abstract
Primary percutaneous coronary intervention (PPCI)—a therapy intended to restore blood flow after acute myocardial infarction—can also induce myocardial ischemia-reperfusion (I/R) injury, exacerbating cardiomyocyte death. Neutrophil-mediated cardiac tissue damage contributes prominently to the process of myocardial I/R injury. Therefore, limiting neutrophil recruitment and exocytosis may prevent myocardial I/R injury after PPCI. Here, we found out that a neutrophil exocytosis inhibitor Nexinhib20 inhibits both neutrophil adhesion and exocytosis and prevents myocardial I/R injury in a mouse model. Using a microfluidic chamber, we found that Nexinhib20 inhibited interleukin 8 (IL-8)-induced β2 integrin-dependent human neutrophil adhesion under flow. Using dynamic flow cytometry assay, we discovered that Nexinhib20 suppresses intracellular calcium flux and β2 integrin activation after IL-8 stimulation. Western blots of Rac-1-GTP pull-down assay confirmed that Nexinhib20 inhibited Rac-1 activation in leukocytes. In vitro competing assay showed that Nexinhib20 antagonized the binding of Rac-1 and GTP. Using a mouse model of myocardial I/R injury, Nexinhib20 administration after ischemia and before reperfusion significantly decreased neutrophil recruitment and infarct size. Our results highlight the translational potential of Nexinhib20 as a dual-functional neutrophil inhibitory drug to prevent myocardial I/R injury.
This research was supported by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute, USA (R01HL145454, R41HL156322, R44HL152710, and K99HL153678), a Career Development Award from American Heart Association (18CDA34110426), and a startup fund from UConn Health.
High-fat diet-induced immune dysregulation in Th17/regulatory T cells promotes inflammation through protein kinase A (PKA) and PPAR-γ pathways
Authors: Kiran Sonia , Rakib Ahmed , Boddu Geetha , Singh Udai P 
Published: January 2023

Abstract
Obesity is a hallmark around the globe, which is defined as a complex situation associated with various metabolic abnormalities and cardiovascular diseases. The increasing evidence suggests that type 1 inflammation-associated immune cells are dominant in adipose tissue and exert metabolically deleterious impacts. The precise mechanism of alteration of adipose tissue immune system and its effect on metabolic homeostasis is far from clear. We investigated how a high-fat diet (HFD) alters adipose tissue (AT) immune system and influences the inflammation. HFD consumption amends the metabolic parameters including body weight, glucose, and insulin levels. We noticed that there is increased infiltration of Th17 cells, dendritic cells, and macrophages in AT of mice fed HFD as compared to a normal diet (ND). In mice consuming HFD, we also find a reduction in regulatory T cells as compared to ND. We noticed a higher level of proinflammatory cytokines and chemokines in the HFD group as compared to ND. We also noticed an increase in IL-6 and KLF4 expression in the AT of HFD as compared to ND. Further, an increased level of AT protein kinase A in HFD fed and a decrease in PPAR-γ as compared to ND, suggesting acting as a negative regulator of Th17 cell differentiation. Taken together, these results suggest that HFD induces Th17, macrophage, dendritic cells, inflammatory cytokine and reduces Tregs and PPAR-γ to sustain AT inflammation. This study supports a key role of Th17/Tregs dysregulation and macrophages to induce AT inflammation through PKA and PPAR-γ pathways during obesity.
(Supported by NIH grant R01 AI140405).
Supported by NIH grant R01 AI140405.
Farnesol induces protection against CNS inflammatory demyelination and decreases spinal infiltration of CD4+ T-Cells
Authors: Doyle William Jerome , Sell Lacey B , Ramelow Christina C , Kohl Hannah M , Hoffman Kristina R , Bains Jasleen K , Strawn Kevin D , Hervin Theresa , Kirby Trevor O , Gibson K Michael , Roullet Jean-Babtiste , Ochoa-Repárez Javier 
Published: January 2023

Abstract
Multiple Sclerosis (MS) is an autoimmune disease that causes T-cells to attack and degrade the myelin sheath of neurons in the spinal cord and brain. Farnesol is synthesized by plants and mammals and has anti-inflammatory along with neuroprotective activities. We used the MOG35–55 induced c57BL/6 murine EAE (experimental autoimmune encephalomyelitis) model due to model’s neurodegenerative and inflammatory properties. We predicted that farnesol would protect against EAE and increase autoimmunity markers. We collected spinal cords and spleens for flow cytometry analysis at the end of the study. This study found that farnesol significantly reduced spinal infiltration of CD4+ T cells, and increased infiltration of Tregs compared to untreated mice. Interestingly the proportion of CD25+Foxp3+ was increased compared to untreated mice, and statistically significant compared to vehicle treatment. We did not observe significant changes in CD4+, or CD25+Foxp3+ frequencies in the spleens. FOL treatment showed significant increase in CD11b+F4/80+ monocyte-derived macrophages (MDM) and F4/80int granulocytes/monocytes. FOL also showed significant weight retention and reduction of disease severity compared to untreated. These findings show that farnesol helps mediate the invasion of CD4+ T cells in the EAE model. Future studies should study how farnesol affects T-cell activation and differentiation, along with affects on macrophages and dendritic cells.
This work was supported in part by the National Institutes of Health (grant R15NS107743)
Hapten skin sensitization induces development of TLR4-dependent inflammatory monocytes that are required for elicitation of skin contact hypersensitivity responses αααα
Authors: Kish Danielle , Fairchild Robert L 
Published: January 2023

Abstract
Contact hypersensitivity (CHS) to skin sensitization and challenge with haptens is mediated by hapten-primed CD8 T cell populations producing IFN-γ and IL-17. Following hapten challenge these primed CD8 T cells induce hapten-presenting endothelial cells (EC) to produce CXCL1/CXCL2 directing the recruitment and activation of a population of inflammatory monocytes (IM) expressing Gr-1, Ly6C, CXCR2, CD11c, FasL and perforin that are required for hapten-primed CD8 T cell infiltration into the parenchymal skin tissue to mediate CHS. This study investigated mechanisms promoting development of these IM. The IM were absent in the bone marrow of hapten sensitized mice with defective IL-1, TNFα or TLR4 receptor signaling. Sensitized TLR4−/− mice lacked CHS responses to challenge despite equivalent numbers of hapten primed CD8 T cells producing IFNγ and IL-17 in skin-draining lymph nodes as sensitized wild type (WT) mice. IM infiltration into hapten challenged skin of sensitized TLR4−/− was absent at 6 hrs. post-challenge and was accompanied by absent skin mRNA expression of CXCL1, CXCL2, IFNγ, GCSF, TNFα, and CCL20. Whereas hapten primed CD8 T cells from sensitized TLR4−/− mice transferred CHS responses to challenged naïve WT mice, transfer of hapten-primed WT CD8 T cells to naïve TLR4−/− mice failed to elicit CHS responses. IM isolated from the bone marrow of sensitized WT mice and transferred at hapten challenge to sensitized TLR4−/− mice restored the absent CHS response and challenged skin expression of CXCL2, IFNγ, and G-CSF mRNA. These results indicate that TLR4 signaling is required for the bone marrow development of IM that are critical for hapten-primed CD8 T cell infiltration into challenged skin during elicitation of CHS responses.
Role of Mycoplasma pneumoniae CARDS toxin in inducing mitochondrial damage and inflammation.
Authors: Benavides Andrea Milenia , Liendo Nathaniel Steven , Segovia Jesus A 
Published: January 2023

Abstract
Known for its ability to cause damaging airway inflammation and decreased lung compliance, Mycoplasma pneumoniae does so through the production of the Community-Acquired Respiratory Distress Syndrome Toxin (CARDS toxin.) This toxin plays a key role in the inflammation seen during infection. Once M. pneumoniae is able to establish infection in the lungs and produce CARDS toxin, harmful inflammation followed by cell death and tissue injury follows. Although CARDS toxin is known to have vacuolating and ADP-ribosylating properties, the exact mechanism by which it triggers an inflammatory response is still being elucidated. Experimental evidence from our lab supports that CARDS toxin can localize to the mitochondria in vitro, and this localization likely triggers mitochondrial damage and an increase in cell death. In our current study, recombinant CARDS toxin was administered to lung epithelial cells and macrophages exogenously, as well as endogenously via the expression of the CARDS toxin gene on a mammalian expression plasmid. Endogenously-expressed CARDS toxin was analyzed by western blot. Additionally, markers of mitochondrial damage and cytokine production were measured. The ADP-ribosylation and vacuolation properties of CARDS toxin were also tested for their ability to trigger inflammatory cytokine production. Our results support our hypothesis that CARDS toxin localization to the mitochondria is required to trigger mitochondrial damage and thus promote inflammation. By better understanding the mechanism through which CARDS toxin affects the mitochondria, we will gain more insight into how M. pneumoniae infects the host, and which therapeutic strategies could be most effective for future outbreaks.
Supported by grant from NIH T34GM008073
Epithelial cell-specific role of HMGB1 in murine lungs with muco-obstructive lung disease
Authors: Mao Yun , Choudhary Ishita , Patial Sonika , Saini Yogesh 
Published: January 2023

Abstract

Introduction
Mucoobstructive lung diseases are characterized by defective mucociliary clearance, mucin hypersecretion, and mucoobstruction. High mobility group box 1 protein (HMGB1) plays a key role as an inflammatory mediator. However, the role of HMGB1 in mucoobstructive lung diseases remains unclear. Using Scnn1b-Tg+ mice, a mouse model of cystic fibrosis, we hypothesized that the airway epithelial cell-specific HMGB1 acts as an anti-inflammatory mediator in the Scnn1b-Tg+ lungs.

Methods
Airway epithelial cell-specific HMGB1-deficient (CCSP-iCre+/Hmgb1flox/flox) and control (CCSP-iCre− /Hmgb1flox/flox) mice were generated. The bronchoalveolar lavage fluid (BALF) and lung tissue were collected for endpoints analyses.

Results
Compared with wild-type (WT) mice, HMGB1 expression was significantly increased in BALF and airway epithelial cells of Scnn1b-Tg+ mice. Unlike HMGB1-sufficient Scnn1b-Tg+ mice, HMGB1-deficient Scnn1b-Tg+ mice exhibited enhanced lung inflammation evident from the elevated total protein and dsDNA contents in the BALF. HMGB1 deletion in airway epithelial cells in Scnn1b-Tg+ mice also exaggerated immune cell recruitment, which was accompanied by increased levels of chemokines and cytokines, including KC, G-CSF, MCP-1, MIP-2, MIP-1α, MIP-1β, and IP-10. Furthermore, HMGB1 deletion in airway epithelial cells in Scnn1b-Tg+ mice enhanced the type 2 inflammation manifested by increased levels of Th2 cytokines such as IL-4 and IL-5. Additionally, HMGB1-deficient Scnn1b-Tg+ mice showed increased airway mucus plugging and impaired bacterial clearance.

Conclusion
Epithelial cell-derived HMGB1 may play an anti-inflammatory role in murine lungs with mucoobstructive lung disease.
Supported by NIEHS (RO1, ES030125)
Pulmonary macrophage activation and recruitment in lipopolysaccharide-induced acute lung injury mediates neutrophil infiltration: Role of AhR ligation in intervention
Authors: Holloman Bryan L , Nagarkatti Mitzi , Nagarkatti Prakash 
Published: January 2023

Abstract
CCL2-CCR2 signaling plays an essential role in the recruitment of macrophages and neutrophils following tissue injury. During inflammation, CCR2+ macrophage secretion of CCL2 induces an autocrine effect that leads to an intracellular signaling cascade of macrophages that promotes upregulation of CCL2, CXCL2, and CXCL3 expression, which stimulates the chemotaxis of blood circulating CCR2+ monocytes and CXCR2+ neutrophils to the disease site. Interestingly, the aryl hydrocarbon receptor (AhR) ligand has been shown to regulate effector cell recruitment. Therefore, we studied the effects of the AhR ligand, indole-3-carbinol (I3C) on the recruitment of circulating CCR2+ monocytes and CXCR2+ neutrophils during acute lung injury (ALI). To induce ALI in C57BL/6 mice and Ccr2gfp mice (mice deficient in the CCR2 receptor), they were given 5mg/kg of lipopolysaccharide intranasally. Mice were treated with I3C or vehicle following disease induction. Interestingly, I3C downregulated neutrophils expressing CXCR2 (a receptor associated with neutrophil recruitment) and CCR2+ macrophages in lungs of C57BL/6 diseased-mice. Furthermore, to determine if CCR2+ macrophages recruit CXCR2+ neutrophils, we induced ALI in Ccr2gfp mice. Abolishing the expression of CCR2 eliminated the recruitment of CXCR2+ neutrophils to the lungs during ALI. Interestingly, scRNASeq of macrophage/monocyte cells showed that I3C reduced expression of CXCL3. CXCL3 gene translates into the chemokine CXCL3, which binds to CXCR2 and is involved in neutrophil recruitment to the disease site. These findings suggest that CCR2 macrophages are involved in the recruitment of CXCR2+ neutrophils, and the AhR ligand I3C can regulate immune cell trafficking capabilities.
Supported by NIH grants P01AT003961, P20GM103641, R01ES030144, R01AI129788, R01AI123947, R01AI160896 and R01AI123947-S2
T-cell-derived Exosomal Proteins ECP and BPI Induce Cytokines and Tissue Inflammation in Systemic Lupus Erythematosus
Authors: Chuang Huai-Chia , Tan Tse-Hua 
Published: January 2023

Abstract
T cells play critical roles in the pathogenesis of systemic lupus erythematosus (SLE). Serum-derived exosomes are increased in human SLE patients and are correlated with disease severity; however, the property of T-cell-derived exosomes from SLE patients remains unclear. We characterized proteins of SLE T cell-derived exosomes by exosome MACSPlex analysis and proteomics using T-cell supernatants from human SLE patients and healthy controls. We identified two exosoaml proteins, eosinophil cationic protein (ECP, also named human RNase 3) and bactericidal/permeability-increasing protein (BPI), which were overexpressed in SLE T-cell-derived exosomes and T cells. Both T-cell-specific ECP transgenic (Lck-ECP Tg) and BPI transgenic (Lck-BPI Tg) mice displayed multi-tissue inflammation. Lck-ECP and Lck-BPI Tg mice displayed early induction of serum IFN-γ levels and IL-1β levels, respectively. Single-cell RNA sequencing (scRNA-seq) showed the induction of IFN-γ mRNA and inflammatory pathways in ECP Tg T cells. ScRNA-seq also showed the reduction of Treg population in BPI Tg T cells; conversely, Treg differentiation was enhanced by BPI knockout. Remarkably, adoptively transferred ECP-containing or BPI-containing exosomes stimulated serum autoantibodies levels and induced nephritis/nephritis/arthritis in the recipient mice. Collectively, ECP or BPI overexpression in T-cell-derived exosomes or T cells are novel biomarkers and pathogenic factors for human SLE nephritis, hepatitis, and arthritis.
TH9-derived IL-9 promotes CCR2-dependent mast cell accumulation in the allergic lung
Authors: Pajulas Abigail , Kaplan Mark H 
Published: January 2023

Abstract
Allergic asthma is a chronic lung disease characterized by airway hyperresponsiveness and cellular infiltration that is exacerbated by IgE-dependent mast cell activation. Our work in mouse models of allergic airway inflammation identified interleukin-9 (IL-9)-producing T helper 9 (TH9) cells as important effector cells in promoting mast cell accumulation in the lungs. However, the precise mechanism of IL-9-mediated mast cell expansion remains unclear. Here, we demonstrate that intranasal recombinant IL-9 expands, while blockade of IL-9 reduces, mast cell progenitor numbers in the lungs and the bone marrow. These findings suggests that there are systemic effects of local IL-9 production in the allergic lung. Using adoptive transfer models and newly generated mice with an inactivation of the IL-9 gene restricted to T cells generated by CD4-Cre/loxP-mediated targeting of the IL-9 gene, we show that TH9 cells promote mast cell progenitor and mature mast cell recruitment from the bone marrow to the lungs in a chemokine receptor 2-dependent manner. Our research further demonstrates that T cell-derived IL-9 is critical for mast cell-mediated airway hyperresponsiveness. Together, these findings define a contribution of T cell-derived IL-9 in promoting mast cell expansion and function in allergic airway inflammation. Therefore, IL-9 may be a promising therapeutic target for targeting mast cell-specific pathologies.
Supported by grants from NIH (R01 AI129241, T32 AI060519)
Cytotoxic CD4+ tissue-resident memory T cells are associated with asthma severity.
Authors: de la Mata Sara Herrera , Ramírez-Suástegui Ciro , Mistry Heena , Kyyaly Mohammad A , Simon Hayley , Liang Shu , Lau Laurie , Barber Clair , Mondal Monalisa , Arshad Syed Hasan , Kurukulaaratchy Ramesh J , Vijayanand Pandurangan , Seumois Grégory 
Published: January 2023

Abstract
Patients with severe uncontrolled asthma represent a distinct endotype with persistent airway inflammation and remodeling that is refractory to corticosteroid treatment. To determine T cell subsets and effector molecules that drive pathogenesis of severe asthma, we performed single-cell transcriptome analysis of &gt;50,000 airway CD4+ T cells isolated from bronchoalveolar lavage (BAL) samples from 30 patients with mild and severe asthma. We observed striking heterogeneity in the nature of CD4+ T cells present in asthmatics’ airways with tissue-resident memory (TRM) cells making a dominant contribution. Notably, in severe asthmatics a subset of CD4+ TRM cells (CD103-expressing) was significantly increased, comprising nearly 65% of all CD4+ T cells in the airways of male patients with severe asthma when compared to mild asthma (13%). This subset was enriched for transcripts linked to T cell receptor (TCR) activation (HLA-DRB1, HLA-DPA1, CD40LG) and cytotoxicity (GZMB, GZMH), and following stimulation expressed high levels of transcripts encoding for pro-inflammatory non-TH2 cytokines (CCL3, CCL4, CCL5, TNF, LIGHT) that could fuel persistent airway inflammation and remodeling. Our findings indicate the need to look beyond the traditional T2 model of severe asthma to better understand the heterogeneity of this disease.
This work was supported by (i) NIH research grant R01HL114093 (PV) and equipment grants (S10RR027366 - BD FACSAria Fusion, and S10OD025052 - Illumina Novaseq 6000); the William K. Bowes Jr. Foundation (P.V.). The WATCH study is supported by the Southampton NIHR Biomedical Research Centre and the Southampton NIHR Clinical Research Facility which are funded by the NIHR and are a partnership between the University of Southampton and University Hospital Southampton NHS Foundation Trust.
Robust homotypic and heterosubytpic immunity against Influenza A Virus in mice lacking Th1/Tc1 transcriptional machinery
Authors: Dhume Kunal , Gallahan Samatha , McKinstry Karl Kai 
Published: January 2023

Abstract
T cell responses against Influenza A Virus (IAV) are dominated by IFN-γ producing CD4 (Th1) and CD8 (Tc1) cells with little IL-17 production. However, loss of the transcription factors T-bet (Tbx21), the master Th1 regulator, and its paralog, Eomesodermin (Eomes), that influences both Th1 and Tc1 functionality, unleashes a strong Th17/Tc17 response while nearly eradicating IFN-γ production and other Th1/Tc1 hallmarks of antiviral T cells. Although Tbx21−/−Eomes−/− mice infected with LCMV were shown to succumb to Tc17 mediated wasting disease, we find that Tbx21−/−Eomes−/− mice survive primary H1N1 IAV infection and clear the virus with similar kinetics as do wild type (WT) mice. Long-lived IAV-specific IgG titers are also similar between Tbx21−/−Eomes−/− and WT mice, correlating with comparable follicular T helper cell responses. Furthermore, primed Tbx21−/−Eomes−/− mice maintain robust homotypic protection against supralethal H1N1 rechallenge indicating highly functional humoral immunity. Strikingly, H1N1-primed Tbx21−/−Eomes−/− mice also survive supralethal H3N2 IAV challenge, indicating intact heterosubtypic immunity as judged by similar viral control, weight loss kinetics and remarkably, no differences in immunopathology versus WT mice despite an overwhelming Th17/Tc17-biased inflammatory response. This cross-protection is T cell dependent as H1N1-primed Tbx21−/−Eomes−/− mice depleted of CD4 and CD8 T cells do not recover or control the H3N2 challenge virus. Our observations thus support that T-bet- and Eomes-independent effector T cells can provide robust long-term protection, potentially extending the available mechanisms for vaccines to target T cell-mediated immunity against IAV.
Supported by grants from NIH (R21AI146647)