bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myeloid-derived suppressor cells modulate aortic aneurysm formation via CXCR2 and IL-17 signaling
Authors: Sharma Ashish Kumar , Elder Craig , Su Gang , Lu Guanyi , Qi Xiaoyan , Jiang Zhihua , Moldawer Lyle Leonard , Efron Philip , Upchurch Gilbert R 
Published: January 2023

Abstract
Aortic aneurysm formation is associated with vascular inflammation and remodeling mediated via CD4+ T cell-secreted IL-17A production. Our hypothesis is that innate myeloid-derived suppressor cells (MDSCs), which are a heterogeneous population of myeloid precursor and progenitor cells, exhibit an immunoregulatory role in the progression of aortic inflammation during abdominal aortic aneurysm (AAA) formation. The trafficking and migration of MDSCs to the aortic tissue and role of CXCR2 and programmed death-1 (PD-1) receptor signaling was deciphered using an in vivo elastase-treatment model of AAA as well as in vitro co-culture experiments. We used an established murine AAA model of topical elastase-treatment in the present study. Preliminary data showed that elastase-treatment of C57BL/6 (wild-type; WT) mice resulted in significant increase in infrarenal aortic diameter causing AAA formation on day 14 that was significantly inhibited by a combined treatment with anti-CXCR2 and PD-1 antibodies. A multi-fold increase in MDSCs (CD11b+Gr-1+) in aortic tissue of elastase-treated WT mice on days 7 and 14 occurred compared to controls. Co-culture of MDSCs with aortic endothelial cells in the presence of anti-CXCR2 antibody inhibited the transmigration of MDSCs through the endothelial barrier. Moreover, transient elastase treatment of co-cultures of anti-CD3/CD28 treated mononuclear cells with MDSCs significantly enhanced IL-17A secretion compared to cultures without MDSCs. Our results indicate that MDSCs may play a contributory role in aortic inflammation by trafficking in a CXCR2-dependent manner and promotion of IL-17A secretion, signifying the importance of MDSC-mediated immunoregulation of aortic aneurysms.
A natural mouse model reveals genetic determinants of Systemic Capillary Leak Syndrome (Clarkson disease)
Authors: Xie Zhihui , Raza Abbas , Chan Eunice , Chen Wei-Sheng , Scott Linda M , Eisch A. Robin , Krementsov Dimitry N , Rosenberg Helene F , Parikh Samir M , Blankenhorn Elizabeth P , Teuscher Cory , Druey Kirk M 
Published: January 2023

Abstract
The Systemic Capillary Leak Syndrome (SCLS, Clarkson disease) is a disorder of unknown etiology characterized by recurrent episodes of vascular leakage of proteins and fluids into peripheral tissues, resulting in whole-body edema and hypotensive shock. The pathologic mechanisms and genetic basis for SCLS remain elusive. Here we identify an inbred mouse strain, SJL, which recapitulates cardinal features of SCLS, including susceptibility to histamine- and infection-triggered vascular leak. We named this trait “Histamine hypersensitivity” (Hhs/Hhs) and mapped it to Chromosome 6. Hhs is syntenic to the genomic locus most strongly associated with SCLS in humans (3p25.3), revealing that the predisposition to develop vascular hyperpermeability has a strong genetic component conserved between humans and mice and providing a naturally occurring animal model for SCLS. Genetic analysis of Hhs may reveal orthologous candidate genes that contribute not only to SCLS, but also to normal and dysregulated mechanisms underlying vascular barrier function more generally.
The complex allergen house dust mite (HDM) dramatically increases the abundance of the autophagy cargo adapter SQSTM1/p62 in macrophages and suppresses Torin 1-induced degradative autophagy
Authors: Gao Hongjuan , Qi Xiulan , Jackson William , Keegan Achsah D 
Published: January 2023

Abstract
Autophagy is an essential homeostatic process involving degradation of intracellular components, including soluble proteins, aggregated proteins, organelles, macromolecular complexes and foreign bodies. Several components of the autophagy pathway have been linked to allergic asthma and macrophage phenotypes, however the contribution of autophagy to these processes is unclear. We previously showed that house dust mite (HDM) increased the number of fluorescent foci (autophagosomes) in bone-marrow derived macrophages (BMM) in a manner similar to the autophagy inducer Torin 1. Further, electron microscopy revealed an increase in double membraned vesicles in response to HDM and Torin 1. While Torin induced a specific increase in lipidated LC3, treatment with HDM caused equal increases in both non-lipidated and lipidated LC3. Torin 1 stimulated autophagic degradation as measured by reduction of SQSTM1/p62. In contrast, SQSTM1/p62 levels increased dramatically in response to HDM. The increase was blocked by actinomycin D and cycloheximide indicating that new gene transcription and protein synthesis is required for the HDM-induced effect. HDM-stimulated increase in SQSTM1/p62 was also observed in alveolar macrophages treated in vitro. An increase in SQSTM1/p62 is often interpreted as a block in autophagic degradation. Indeed, we observed that in the presence of HDM, Torin 1 treatment did not lead to the loss of SQSTM1/p62 below baseline; however, the protein did not accumulate to the high level observed in the HDM-alone treatment group. Our results suggest that HDM engages autophagy machinery at multiple points, both inducing expression of SQSTM1/p62 and suppressing its degradation.
Resolvin D2 Promotes the Resolution of Allergen-Induced Lung Inflammation
Authors: Peh Hong Yong , Bruggemann Thayse R , Ho Wanxing Eugene , Cheng Chang , Tan WS Daniel , Wong WS Fred , Levy Bruce D 
Published: January 2023

Abstract

Background
Asthma is a chronic inflammatory disease without complete resolution. The production of specialized pro-resolving mediators (SPMs) is defective in asthma, so they represent a potential therapeutic opportunity. We hypothesize that docosahexaenoic acid derived resolvin D2 (RvD2) can promote the resolution of asthma.

Methods
BALB/c mice were challenged intra-tracheally with house dust mite (HDM). Bronchoalveolar lavage (BAL) fluid was collected at predefined protocol endpoints for peak inflammation and during resolution. To determine impact on resolution, some mice were given RvD2 (100 ng, intra-nasally) for 2 days after the last HDM challenge, and the resolution index for eosinophils and other markers were calculated.

Results
Airway HDM challenge led to marked increases in BAL eosinophils and BAL fluid pro-inflammatory cytokine and chemokine levels. Histology demonstrated changes in airway inflammation and mucous cell metaplasia in HDM-challenged lungs. NF-κB and Nrf2 expression were increased the lungs of HDM allergic mice. Compared to vehicle, treatment with RvD2 significantly decreased BAL inflammatory macrophage and eosinophil counts, and accelerated the resolution of HDM-evoked inflammation with a marked decrease in the resolution index for BAL eosinophils from 5 days to 1 day. Interestingly, RvD2 attenuation of eosinophils specifically targeted the inflammatory eosinophil population, but not the resident eosinophils. The impact of RvD2 on cytokine expression and NF-kB and Nrf2 activity is under current investigation to determine mechanisms for RvD2’s pro-resolving actions.

Conclusion
RvD2 promotes resolution of allergen-induced inflammation in a murine model of allergic asthma.
Evaluation of the skin sensitizing potential of gold nanoparticles and the impact of established dermal sensitivity on the pulmonary immune response to various forms of gold
Authors: Roach Katherine Adair , Anderson Stacey , Stefaniak Aleksandr , Shane Hillary L , Roberts Jenny R 
Published: January 2023

Abstract
Gold compounds are associated with diverse immune effects, including allergy. Whether gold nanoparticles (AuNP) cause similar effects remains unknown. To address this, three in vivo studies were performed. AuNP (29nm)dermal sensitization potential was assessed via Local Lymph Node Assay (LLNA) along with soluble gold salts (AuCl3) and larger particles (Au, 942nm). AuCl3 caused lymph node (LN) expansion (SI 10.9), whereas Au and AuNP did not, indicating minimal potential for dermal sensitization. Next, pulmonary immune effects of AuNP (10μg, 30μg, 90μg) were assessed 1d, 4d, 8d post-aspiration. AuNP had no effect on lung injury or inflammation, but did increase LN CD4+ T- and B-cells by 4d. Finally, mice were dermally sensitized to AuCl3 (d1-3), then aspirated 1× (d10),2× (d10, 14), or 3× (d10, 14, 18) with Au or AuNP in doses normalized for mass or surface area (SA), to assess impact of existing contact sensitivity on lung immune responses. In dermally sensitized groups, increased BAL lymphocytes were seen after two and three aspirations, which correlated to the administered SA. The highest AuNP dose caused the greatest increase in total BAL lymphocytes, as well as increased number, proportion, and activation of BAL/LN CD8+ T-cells. Comparatively, the lower SA-based doses of Au/AuNP resulted in elevated numbers of BAL T-cells(predominantly CD4+ phenotype), exposure-dependent increases in serum IgE, and selective expansion/activation of LN CD4+ T- and B-cells, suggestive of a Th2-polarized state. Overall, these findings suggest that AuNP are not likely to cause allergic sensitization; however, established contact sensitivity to gold may be associated with increased immune reactivity to AuNP following respiratory exposure.
Diuretics combined with captopril modulate macrophage-induced humoral and contact hypersensitivity responses in mice
Authors: Bryniarski Pawel , Nazimek Katarzyna , Marcinkiewicz Janusz 
Published: January 2023

Abstract

Introduction
The over-activated inflammatory responses of macrophages (Mph) likely increases the risk of hypertension development, while clinically relevant diuretics administered alone or in combination with antihypertensive drugs may possibly exert the immunomodulatory effects. Thus, we investigated the impact of these drugs on macrophage-mediated immunity in mice.

Methodology
CBA mice were treated i.p. with captopril (5 mg/kg) with or without hydrochlorothiazide (10 mg/kg) or furosemide (5 mg/kg) by 8 days. On the third day, mice were i.p. injected with mineral oil and 5 days later Mph were harvested to assess the generation of reactive oxygen species (ROS) and nitric oxide (NO). Mph were also pulsed with sheep red blood cells (SRBC) or hapten and transferred to naive mice for evaluation of their ability to induce humoral or contact hypersensitivity (CHS) reactions, respectively.

Results
Diuretics, when administered alone or with captopril, enhanced ROS, but decreased NO production by Mph. SRBC-pulsed Mph from mice treated with captopril combined with diuretics increased the secretion of antigen-specific antibodies by recipient B cells, while Mph of mice treated with hydrochlorotiazide or furosemide with captopril increased the number of antigen-specific B cells. Captopril reduced CHS ear swelling response and this effect was augmented by diuretics.

Conclusions
Our results showed that diuretics with or without captopril modulate the humoral and allergic cell-mediated immune responses by affecting the function of Mph. Further studies should investigate the clinical effect of these observations.
The study was supported by budget funds for science in 2017-2021 under the “Diamond Grant” program (0168/DIA/2017/46).
Nrf2 suppresses allergic lung inflammation by attenuating the type2-innate lymphoid cell response
Authors: Nagashima Ryuichi , Tanaka Nobuyuki 
Published: January 2023

Abstract
The Keap1-Nrf2 system has an essential role in oxidative-stress responses by inducing a number of cytoprotective genes. Under stress, damaged epithelial cells release cytokines that activate Type 2 Innate lymphoid cells (ILC2s), which mediate the allergic immune response. Here we investigated the role of the Keap1-Nrf2 pathway in ILC2 homeostasis and allergic inflammation, using Nrf-2-knockout mice. ILC2s from Nrf2-deficient mice showed a transient, upregulated IL-33 response, and underwent hyper-proliferation in response to combined stimulation by IL-33 with IL-2, IL-7, or TSLP. This enhanced proliferation was correlated with an increased activation of downstream signals, including JAK1, Akt, and Erk1/2. In contrast, activating Nrf2 with a chemical inducer (CDDO-Im) decreased the viability of wild-type, but not of the Nrf2-deficient ILC2s. The reduced ILC2 viability resembled that exerted by the corticosteroid dexamethasone; however, unlike the latter, the Nrf2-dependent cell death was mediated by neither caspase 3-dependent apoptosis nor necroptosis. Using a mouse intratracheal IL-33-administration allergy model, we found that the activation of Nrf2 by CDDO-Im in vivo decreased the numbers of pulmonary ILC2s and eosinophils. These findings indicated that Nrf2 is an important regulator of the allergic response, by determining the survival and death of ILC2s, and suggest that Nrf2 activation is a potential therapeutic strategy for steroid-resistant allergy alleviation.
Defense mechanisms during respiratory infections in hosts with underlying asthma
Authors: Samarasinghe Amali , LeMessurier Kim , Tiwary Meenakshi 
Published: January 2023

Abstract
Influenza can often be complicated by superinfections by bacteria such as Streptococcus pneumoniae. While these opportunistic bacterial pathogens do co-infect during seasonal influenza epidemics, the relationship is exaggerated during pandemic influenza virus infections as documented during all four previous influenza pandemics. Approximately 29–55% of hospitalized patients with Swine Flu with severe disease had a bacterial co-infection; however, asthmatics that were hospitalized during this influenza pandemic were less likely to have co-infections. We built a mouse model that recapitulated these intriguing epidemiologic findings that underlying asthma protected the host from severe morbidity and mortality associated with IAV and S. pneumoniae co-infection. These mice had significantly reduced bacterial load in the lungs, increased eosinophils and macrophages in the airways, but reduced tissue inflammation and scarring compared to non-allergic co-infected mice. We hypothesized that TH2-biased programming of eosinophils within the lungs of allergic mice heightened their immune responses to invading respiratory pathogens. We found that allergen sensitization and IAV exposure activated eosinophils marked by upregulation of CD69, ICAM-1, and IL-5Rα, maintained their viability, and enhanced bacterial uptake through receptor-mediated phagocytosis. Activated eosinophils prevented IAV-induced cytopathology on respiratory epithelia and were able to inhibit the growth and kill S. pneumoniae without undergoing cytolysis. Our data suggest a novel pathway by which eosinophils in hosts with asthma may protect the host from severe diseases induced by respiratory pathogens by inhibiting viral-bacterial synergy.
Neutrophils are actively involved in the regulation of inflammation and the maintenance of surfactant homeostasis during cigarette smoke exposure
Authors: Milad Nadia , Pineault Marie , Lechasseur Ariane , Routhier Joanie , Beaulieu Marie-Josée , Aubin Sophie , Morissette Mathieu 
Published: January 2023

Abstract

Rationale
Exposure to cigarette smoke induces inflammation marked by rapid and sustained neutrophil infiltration as well as pulmonary surfactant damage. However, the extent to which neutrophils contribute to the clearance of surfactant and the inflammatory response to cigarette smoke exposure is not fully understood.

Objective
We aim 1) to assess the capacity of neutrophils to internalise surfactant and 2) to determine whether neutrophil depletion has an effect on surfactant homeostasis and the inflammatory response induced by cigarette smoke exposure.

Methods/Results
1) By incubating cells isolated from the bronchoalveolar lavage of cigarette smoke exposed mice with fluorescently labelled surfactant (NBD-phosphatidylcholine), we observed via microscopy significant in vitro surfactant internalisation by neutrophils. Similarly, neutrophils absorbed labelled surfactant delivered intranasally in vivo as measured by flow cytometry. 2) Neutrophil depletion during cigarette smoke exposure via injection of depleting antibodies (anti-Ly6G or anti-Gr-1) led to exaggerated pro-inflammatory cytokine release (IL-1α, CCL2, GM-CSF and G-CSF) and increased macrophage protease expression (Mmp12). Depletion of neutrophils also led to increased surfactant protein levels (SP-A and SP-D).

Conclusions
Our results show that neutrophils recruited to the lungs during cigarette smoke exposure internalise pulmonary surfactant and that their absence leads to exacerbation of the pro-inflammatory response and alterations to surfactant composition. Therefore, neutrophils seem to play a crucial role in the maintenance of pulmonary homeostasis following cigarette smoke exposure.
Plasmacytoid dendritic cells (pDCs) and IFN-α production in aged squirrel monkeys (Saimiri boliviensis boliviensis) stimulated with Class C CpG Oligodeoxynucleotides
Authors: Nehete Pramod N , Chitta Sriram , Nehete Bharti P , Williams Lawrence E , Wisniewski Thomas , Scholtzova Henrieta 
Published: January 2023

Abstract
Synthetic CpG oligodeoxynucleotides (ODNs) with defined CpG motifs and immunomodulatory properties signal through an endosomal membrane-based type of pattern recognition receptor (PRR), the Toll-like receptor 9 (TLR9), that has been identified in dendritic cells (DCs), B cells, and other human immune cell types. CpG-ODNs influence several signaling pathways, leading to cytokine production in many mammalian species that make CpG ODNs suitable as therapeutic interventions in a variety of human disease conditions. The squirrel monkey (SQM), a well-established New World non-human primate (NHP) model is known to be used for studying various diseases such as Alzheimer’s disease (AD), malaria, and transmissible spongiform encephalopathies (Creutzfeldt-Jacob disease). In the present study, we generated the first report of immunoregulatory activity of class C CpG-ODN in aged squirrel monkey. CpG-ODN exhibits very potent effects on squirrel monkey immune cells by inducing IFN-γ/IFN-α from peripheral blood mononuclear cells and demonstrates accelerated kinetics of activity. In addition, class C CpG-ODN specifically activates pDCs to undergo maturation and secrete cytokines, including high levels of IFN-α. To best to our knowledge, this is the first documentation describing immune status in squirrel monkeys immunized with C class CpG-ODN by concentrating on lymphocyte surface antigen expression and function. Overall, our findings provide critical data regarding the immunomodulatory potential of CpG-ODN in this NHP model allowing for future therapeutic trials of innate immunity stimulation via TLR9 agonists for diverse indications including AD therapeutics.
CD71+ erythroid cells inhibit inflammatory cytokines secretion of monocytes during extracorporeal membrane oxygenation
Authors: Han Junyan , Cao Yu , Hao Xing , Fan Lina , Du Zhongtao , Hou Xiaotong , Zeng Hui 
Published: January 2023

Abstract
Extracorporeal membrane oxygenation (ECMO) has been widely used clinically to support heart and/or lung function. ECMO exposes the blood to non-endothelial cell surface and trigger systemic and local inflammatory responses. Monocytes are proved to contribute to ECMO-induced inflammatory responses and infection. In this study, we investigated the inflammatory cytokines secretion of monocytes and explored the possible mechanisms.

Materials and Methods
Fifty seven patients undergoing ECMO support were enrolled at Beijing Anzhen Hospital, Capital Medical University. Peripheral blood samples from patients were collected into EDTA tubes after the ECMO support days 1, 2, 3, 5 and 7 and post weaning. The ability of monocytes to secret cytokines and the percentage of CD71+ cells were examined by flow cytometry. The effects of CD71+ erythroid cells on the ability of secrete cytokines of monocytes were explored by depleting CD71+ erythroid cells with magnetic beads sorting. The mechanisms of inhibitory effect of CD71+ erythroid on cytokines secretion of monocytes were investigated with Transwell coculture system.

Results
In patients supported with ECMO, the ability of monocytes to secrete cytokines, TNF-a, IL-6 and IL-1b, was significantly decreased compared with healthy controls. It was accompanied by the increased percentage of CD71+ erythroid cells. Depletion of CD71+ erythroid cells rescued the ability of monocytes to secrete cytokines. CD71+ erythroid cells inhibited the cytokines secretion of monocytes in cell-to-cell contact manner.

Conclusion
The enriched CD71+ erythroid cells in peripheral blood inhibited inflammatory cytokines secretion of monocytes in cell-to-cell contact manner in patients supported with ECMO.
Mast cells play a critical role in driving prostatic inflammation in Lower Urinary Tract Symptoms associated with Benign Prostatic Hyperplasia
Authors: Pattabiraman Goutham , Bell-Cohn Ashlee Justine , Murphy Stephen Fintan , Schaeffer Anthony J , Thumbikat Praveen 
Published: January 2023

Abstract

Background
Prostatic inflammation is a key contributor to lower urinary tract symptoms (LUTS). An intraurethral infection with a uropathogenic isolate of E. coli (CP1) results in clinical signs of benign prostatic hyperplasia (BPH) and LUTS as demonstrated by increased urinary dysfunction, prostate inflammation and fibrosis. In this study we study the importance of mast cells in driving prostate inflammation in BPH/LUTS and the therapeutic benefit of mast cell neutralization on the disease.

Results
We observed increased mast cell infiltration and activation associated with increased fibrosis in prostate tissues from BPH patients and CP1 infected mice as identified by toluidine blue and picrosirius staining. To assess the role of mast cell activation, inhibition was performed using a combination of a mast cell stabilizer and histamine 1 receptor (H1R) antagonist at an early and late time point post CP1 infection. Treatment with this combination resulted in a decrease of activated mast cells in prostate tissues of infected mice. Furthermore, the prostate of these mice showed decreased prostate fibrosis and inflammation as assessed by picrosirius red staining and flow cytometry for immune cell infiltrates. Finally, we observed that this combination treatment can ameliorate the urinary dysfunction previously observed in response to CP1 infection, as assessed using unconscious terminal cystometry and bladder voiding function measurements.

Conclusions
These results provide evidence of the critical role played by mast cells in the development of prostate inflammation in BPH/LUTS. A combination therapy of mast cell stabilizer and H1R antagonist maybe a useful target for therapeutic intervention in men with BPH/LUTS.