bluuebunny/crossref_metadata_2025_split huggingface dataset:
Toll-like receptor 7 protects against intestinal inflammation and restricts the development of tissue-resident memory CD8+ T cells
Authors: Hamade Hussein , Stamps Jasmine , Thomas Lisa , Stamps Dalton , Tsuda Masato , Oshima Naoki , Wong Michelle , Salumbides Brenda , Jin Caroline , Nunnelee Jordan , Targan Stephan R , Michelsen Kathrin S 
Published: January 2023

Abstract
The maintenance of intestinal homeostasis depends on a complex interaction between microbiota, intestinal epithelial barrier, and the immune system. Alteration in of one of these components could lead to the development of inflammatory bowel diseases (IBD). Norovirus infection of mice with a mutation in the Crohn’s disease susceptibility gene Atg16L1 induces intestinal inflammation. Moreover, persistent norovirus infection leads to intestinal virus-specific CD8+ T cells responses. However, the role of the enteric virome in IBD is still poorly understood. Toll-like receptor 7 (TLR7) recognizes single-stranded RNA viruses. Here, we investigate the role of TLR7 in intestinal homeostasis and inflammation. At steady state, Tlr7−/− mice have an approx. 10-fold increase in small and large intestinal lamina propria (LP) granzyme B+ tissue-resident memory (Trm) CD8+ T cells compared to WT mice (WT: 5.5, Tlr7−/−: 59.5 %, p &lt; 0.005), reminiscent of persistent norovirus infection. Furthermore, Tlr7−/− mice were more susceptible to dextran sulfate sodium (DSS) colitis with more severe inflammation (Histoscore: WT: 7.6, Tlr7−/−: 12.7, p &lt; 0.005), increased disease activity index (WT: 5.5, Tlr7−/−: 7.4, p &lt; 0.05), and increased secretion of IFNg (WT: 5.2, Tlr7−/−: 24.2 ng/ml, p &lt; 0.005) and TNFα (WT: 108.6, Tlr7−/−: 191.8 pg/ml, p &lt; 0.05). Increased colonic inflammation was associated with increased LP Trm CD8+ T cells (WT: 3.9, Tlr7−/−: 42.0 %, p &lt; 0.005). Our data shows that TLR7-deficiency promotes the development of LP Trm CD8+ T cells and increases susceptibility to DSS colitis. In conclusion, TLR7 plays an important role in maintaining immune response to intestinal viruses and protects against development of colitis.
Integrin β7 is required for B cell migration and regulation of the intestinal microbiota during colitis
Authors: Tyler Christopher J , Guzman Mauricio , Lundborg Luke , Yeasmin Shaila , Rivera-Nieves Jesus 
Published: January 2023

Abstract
The incidence of ulcerative colitis (UC) is increasing worldwide. A proven therapeutic strategy for UC is the inhibition of leukocyte trafficking via blockade of integrin β7. Despite this, the mechanism of action of vedolizumab (anti-α4β7) is poorly defined. Clear definitions of the immune subsets targeted by vedolizumab are essential for understanding the pathogenesis of UC, and development of biological endpoints for assessing treatment efficacy.

Methods
The IL-10−/− colitis model was crossed with integrin β7 deficient mice, and clinical features and histological scores were recorded. Flow cytometry of B-cell populations was conducted in colonic cell isolations. 16S bacterial sequencing was conducted on intestinal content.

Results
IL-10−/−β7−/− mice displayed increased mortality compared to IL-10−/− mice at 12 weeks and uniformly developed rectal prolapses. IL-10−/−β7−/− mice displayed increased colonic inflammatory indices (n&gt;10, p&lt;0.001), associated with a reduced B-cell, but normal T-cell, intestinal infiltrate (n&gt;6, p&lt;0.001). IL-10−/−β7−/− mice displayed a resulting IgA deficiency and significant alterations to the resident microbiota. The presence of systemic bacterial infection was observed. Blockade of the α4β7 ligand MAdCAM-1 in IL-10−/− mice resulted in a parallel phenotype.

Discussion
Integrin β7 deficiency results in a worsening of colitis in mice, resulting from a B-cell deficit in the inflamed colon and control the microbiota, via IgA. B-cells are largely ignored in the field of IBD and the potential complications associated with chronic integrin blockade. Our data suggests that the role of integrin β7 on B-cell migration may have important implications on the pathogenesis of colitis in mice and humans.
Antagonists of chemokine receptor CCR9 synergize with anti-TNFα immunotherapy to reduce inflammation in the MDR1a−/− mouse model of colitis
Authors: Campbell James J , Ertl Linda S , Ebsworth Karen J , McMahon Jeffrey P , Zhang Penglie J , Chhina Vicky J , Charo Israel F , Schall Thomas J 
Published: January 2023

Abstract
The development of anti-TNFα immunotherapies has led to great advances in quality of life for Crohn’s and colitis patients, and has allowed a reduction in steroid use for these diseases. However, a significant proportion of IBD patients is resistant to anti-TNFα agents, or becomes resistant over time. Preclinical research and clinical trials suggest that CCR9 antagonism can effectively reduce colon inflammation. CCR9 is expressed on a subset of T cells dedicated to intestinal trafficking. Antagonism of this receptor inhibits the accumulation of T cells within inflamed intestinal epithelium and lamina propria. Since anti-TNFα and CCR9 antagonists act through entirely different mechanisms, we asked whether these two approaches might synergize and expand the effectiveness and scope of each therapy. We used a piroxicam-accelerated version of the MDR1a−/− spontaneous colitis model in mice. We have found that combined dosing of piroxicam-fed MDR1a−/− mice with a CCR9 antagonist and an anti-TNFα MAb significantly reverses loss of body weight, diarrhea score and colon inflammation. The combined dosing was more effective than anti-TNFα or CCR9 antagonist alone, as measured by colon length/weight ratio, neutrophil accumulation in the colonic epithelium and reversal of the loss in body weight characteristic of this model. These data suggest that combining a CCR9 antagonist with existing anti-TNFα treatment regimens may extend the benefits of anti-TNFα immunotherapy to a larger class of patients suffering from IBD, and may prolong the effectiveness of anti-TNFα immunotherapy for those patients already undergoing such treatments.
Exosomal miRNA19a from primary human nasal epithelial cells induce pro-inflammatory responses of macrophages via RORA
Authors: Shin Cheolhee , Tran Na Ly , Kim Tae Hoon , Kim Sang-Heon , Oh Seung Ja 
Published: January 2023

Abstract
Macrophages are phagocytes that play a critical role in the immune system. They are involved in both innate and adaptive immunity by either removing pathogens or antigen presentation. It has been shown that macrophages are polarized to subgroups with distinct functions, M1 and M2. M1 polarization is characterized by pro-inflammatory and anti-cancer functions, whereas M2 macrophages promote immune suppression and tumor growth. In this study, we investigate that exosomal miRNAs from primary human nasal epithelial cells play roles in airway mucosal microenvironment. Specifically, we demonstrated that the human nasal epithelial cells treated with urban dust modulate airway mucosal microenvironment through upregulation and release of miRNAs. The result shows that the human nasal epithelial cells treated with urban dust altered miRNA expression profile and released miRNAs promotes M1 macrophage polarization. The study will further investigate exosomal miRNA mediated-communications between epithelium and macrophages in airway mucosal microenvironment.
Klebsiella Pneumoniae Mucosal Vaccination Elicits Lung CD4+ TRM cells that are resistant to CD4 depleting antibodies
Authors: Iwanaga Naoki , Sandquist Ivy , Chen Kong , Norton Elizabeth B , Rangel-Moreno Javier , Kolls Jay K. 
Published: January 2023

Abstract

Objective
Mucosal immunization with a Klebsiella pneumoniae (Kp) vaccine elicits noble CXCR6+CD4+ T cells that mediate serotype independent immunity, but the stability of this response is unclear. Thus we conducted experiments to determine if these cells circulate and whether they could be depleted by a depleting anti-GK1.5 mAb.

Methods
Mice were vaccinated via intratracheal with Kp serotype 2 OMPx adjuvanted with heat-labile enterotoxin A1 domain (LTA1) and boosted at 3 weeks after the initial immunization. T-cell responses were evaluated by FACS and ELISPOT. CD4+ T cell depletion in the immunized lung, lymph nodes, and spleen by administering 300ug anti-GK1.5 mAb intraperitoneally was examined using a secondary antibody for anti-GK1.5 mAb. Finally, lung and spleen CD4+ T cells of intratracheally immunized CD45.1+ C57BL/6 mice were transferred to CD45.2+ C57BL/6 mice and Rag2−/− mice.

Results
Immunized lung CD4+ T cells were increased equivalently in both C57BL/6 mice and Cxcr6−/− mice, demonstrating that CXCR6 was dispensable for the formation of lung CD4+ T cells. Splenic CD4+ T cells were &gt; 95% depleted with anti-GK1.5 mAb. In contrast, &lt; 5% of vaccine elicited lung CD4+ T cells were depleted despite being well coated by the antibody, strongly suggesting that these cells are TRM cells. Additionally, using an adoptive transfer model, we found that lung CD4+ T cells preferentially homed to lung compared to splenic CD4+ T cells. We next performed single-cell RNAseq on these cells and elucidated several unique adhesion molecules such as Embigin, Ramp1, Lgals1, and Thy1 besides Cxcr6.

Conclusions
These data support that vaccine strategies can be developed by targeting a unique feature of tissue-resident memory CD4+ T cells in lungs.
IL-25-responsive migratory iILC2s require BATF and stably convert to tissue-resident nILC2s
Authors: Miller Mindy M , Danhorn Thomas , Reinhardt R. Lee 
Published: January 2023

Abstract
Inflammatory ILC2s (iILC2s) are a transient subset of group-2 innate lymphoid cells that migrate to the lung shortly after helminth infection or IL-25 administration. Our recent findings identified the AP-1 factor BATF as the major transcriptional regulator required for iILC2 generation and function. Batf-deficient mice infected with the helminth Nippostrongylus brasiliensis display a selective defect in IL-25-mediated worm clearance and a loss of iILC2s but not nILC2s. This corresponds with the absence of early cytokine production by ILC2s in Batf-deficient mice, indicating the requirement of this transcription factor in ILC2 function. The fate of iILC2s is currently unknown as this subset of ILC2s is found only transiently in the lung following infection. Taking advantage of our finding that Arginase-1 (Arg1) expression can delineate tissue-resident nILC2 (Arg1+) and migratory iILC2 (Arg1−) populations, we used an Arg1 reporter mouse to address whether iILC2s could acquire an Arg1+ nILC2-like phenotype. Upon transfer into a congenic host, sorted Arg1− iILC2s acquired Arg1 expression and further adopted characteristics of nILC2s. These converted cells stably persisted after transfer indicating a potential long-term contribution of migratory iILC2s to the tissue-resident nILC2 pool in the lung.
IL-7 shapes a multifaceted CD8 T cell response to airway Influenza/A infection
Authors: Sheikh Abdalla A , Jackson Jennie , Shim Brian , Plumb Adam , Abraham Ninan 
Published: January 2023

Abstract
The lungs are a site vulnerable to diseases such as cancer, autoimmunity and infections. With each breath, we risk inhaling infectious agents, and as such, airborne diseases are the leading cause of infectious disease-related deaths in the world. In particular, various strains of Influenza virus can infect airway epithelial cells and activate a network of immune cells leading to clearance, or in cases of pandemic strains, an overzealous response that can be fatal.
Adaptive immune cells, particularly cytotoxic CD8 T cell lymphocytes, play a crucial role in controlling viral replication by killing infected cells. Therefore, tight regulation of the cytokines that lead to the proper activation, proliferation and function of these immune cells is necessary to clear infections efficiently while minimizing damage to the host. Interleukin-7 (IL-7) is a cytokine known for its importance in T cell development and survival. While the function of IL-7 in T cell survival is well characterized, how IL-7 shapes T cell effector responses when a pathogen is encountered is less understood.
Using IL-7Rα hypomorph mice in chimeric and adoptive transfer experiments we have found that IL-7 is cell-intrinsically important for the priming of antigen specific CD8 T cells in the draining lymph nodes. We found that IL-7 dictates terminal differentiation, cytokine production and degranulation of CD8 T cells locally in the airways. Drugs that manipulate IL-7 signaling are currently under clinical trial for multiple conditions. Our findings on IL-7 and its effects on lower respiratory diseases will be necessary for expanding the utility of these therapeutics.
Shedding LIGHT and TL1A on fibrosis
Authors: Herro Rana , Croft Michael 
Published: January 2023

Abstract
Anti-inflammatory drugs have so far failed to reduce fibrosis and tissue remodeling in the clinic. Alternatively, 5 TNF inhibitors have been FDA approved to treat different inflammatory diseases and are safe to administer to patients. In human, LIGHT and its receptors have been linked to numerous autoimmune and inflammatory diseases with fibrotic components. We show that blocking LIGHT signaling in isolation is efficient in reducing fibrosis in the skin and lung of mice induced with bleomycin to mimic human SSc and IPF, as well as in 2 severe allergen-driven models of asthma and atopic dermatitis. Neutralizing LIGHT signaling through its receptors by genetic deletion or antibody blocking, dramatically decreased fibrosis in the lungs and skins. Moreover the specific deletion of LIGHT-receptor HVEM on keratinocytes or the therapeutic blocking of LIGHT-HVEM interaction post-disease onset, abrogated skin fibrosis. LIGHT seems to play a central role since it can control the expression of major pro-fibrotic factors such as TSLP, IL-13, TGF-b and Periostin. Also LIGHT alone can induce a fibro-proliferative disorder that mimics human SSc, when administered alone. Lastly we observed an upregulation of LIGHT and its receptors in lung biopsies of patients suffering from asthma, SSc and IPF. More recently, we discovered another TNF family Member called TL1A can also potentiate fibrosis similarly to LIGHT and which signaling can promote tissue remodeling. Using antagonistic fusion proteins to neutralize LIGHT and TL1A signaling, we treated skin fibrosis and observed greater efficacy when LIGHT and TL1A were targeted concomitantly. The relevance of this work to fibrosis therapies associated with asthma, AD, SSc and IPF are tremendous.
The role of RUBCN in exacerbating allergic airway inflammation
Authors: Martinez Jennifer , Oguin Thomas H , Kolb Joseph P , Whitehead Gregory , Thomas Seddon Y , Muse Ginger W , DeGraff Laura Miller , Cook Donald N. 
Published: January 2023

Abstract
Allergic airway inflammation (typified by atopic asthma) is a classic example of type 2 immunity, which can be triggered by non-microbial environmental stimuli, such as allergens. Importantly, type 2 immunity engages the entire affected tissue and can involve the activity of not only immune cells, like Th2 cells and eosinophils, but also non-hematopoietic cells, like epithelial cells. Often, type 2 immunity exists in competition with type 1 immunity, classically defined as the activity of phagocytic cells, such as classically activated “M1” macrophages, and IFNg-producing adaptive immune cells, like CD8+ T cells and Th1 cells. Our past studies have demonstrated that deficiency in LC3-associated phagocytosis (LAP), a non-canonical form of autophagy requiring Rubcn, results in increased type 1 inflammation across a variety of stimuli, suggesting that LAP represents an important mechanism to regulate the inflammatory response. How Rubcn deficiency affects the onset and severity of type 2 immunity, such as allergic airway inflammation, remains unknown. Here, we demonstrate that, in response to house dust extract (HDE)/OVA exposure, lungs from Rubcn−/− mice contain increased levels of Th1 and Tr17 cells (potent regulatory CD4+ T cells that co-express FOXP3 and RORg), decreased Th2 cells, and decreased neutrophils, resulting in overall protection from allergic airway pathology. Rubcn-deficiency was required in non-hematopoietic cells, presumably airway epithelial cells, to exert this protective effect. As approximately 50% of asthmatics suffer from corticosteroid-resistant, neutrophil-mediated inflammation, inhibition of RUBCN could represent a novel therapy for steroid-resistant asthmatics.
Zom-biecoming: Single-Cell RNA-sequencing reveals senescence-like features of alveolar macrophages during aging
Authors: Wu Yue , Zhu Bibo , Zhang Ruixuan , Goplen Nicholas PJ. , Wang Zheng , Li Ying , Cardani-Boulton Amber , Braciale Thomas J , Sun Jie 
Published: January 2023

Abstract
Alveolar Macrophages (AMs) are unique innate immune cells that reside in the alveolar space and accommodate the ever-changing need of the lungs against internal and external challenges. During homeostasis, AMs maintained themselves through self-renewal without the need for input from adult hematopoietic stem cells. Currently, little is known about how aging influences AM dynamics, heterogeneity and self-renewal. To this end, we have performed single-cell RNA sequencing (scRNA-seq) on murine lung AMs (CD11+ Siglec F+) isolated from young (~8w) and aged (~2y) mice. We discovered that despite similar transcriptome in the proliferating cells, AMs from aged mice had reduced proliferation and self-renew ability than those from the young mice. AMs from aged mice also displayed elevated senescence markers such as p16, p21 and p53. Consistently, AMs from aged mice had reduced DNA repair ability, which could contribute to their impaired capacity to pass through the cell cycle checkpoints. Interestingly, AMs from aged mice also possessed reduced pro-apoptotic gene profile. Thus, we hypothesize that the reduced proliferation- and apoptosis-associated gene profiles in aged AMs may lead to the enhanced senescence-like phenotype in those cells. Further validation of the senescence-like phenotype of aged AMs and investigation of how they contribute to lung “inflammaging” are warranted.
Natural killer cells orchestrate angiogenesis
Authors: Wolf Katharine , Bilal Mahmood , Schneiderman Sylvia , Dambaeva Svetlana , Beaman Kenneth D 
Published: January 2023

Abstract
Tumor-associated angiogenesis is accompanied by immunosuppression mediated by tumor cells and the immune microenvironment. Similarly, embryo implantation in the uterus requires both angiogenesis and immunosuppression. Uterine natural killer (NK) cells promote immune tolerance for the allogenic invasion of the embryo during pregnancy. In these studies, we explore the mechanism of NK cell-mediated vascular remodeling. RNA sequencing demonstrates a subpopulation of uterine NK cells that are enriched for proangiogenic genes in the uterus during pregnancy. Ephrin-B2 is a receptor tyrosine kinase well known for promoting angiogenesis in cancer, however, the mechanism for ephrin-B2-mediated angiogenesis in the uterus is not known. NK cells were isolated from the uterus and spleen of mice. Isolated NK cells were characterized for the expression of ephrin-B2 by immunofluorescence and flow cytometry. We show that uterine, but not splenic, NK cells express ephrin-B2. Because uterine NK cells also mediate immunosuppression, uterine NK cells were probed for expression of cytotoxicity markers. Cytotoxic marker CD27 is significantly upregulated in conventional NK cells, but not tissue-resident NK cells. Our data show that tissue resident uterine NK cells express pro-angiogenic marker ephrin-B2 and that these cells are not cytotoxic. This describes a previously unsuspected function for NK cells.
Comparison of the therapeutic effects between topical 8-oxo-2′-deoxyguanosine and steroid in ocular chemical burn experimental model
Authors: Kim Dong Hyun 
Published: January 2023

Abstract

Purpose
To compare the effects of topical 8-oxo-dG and steroids on ocular chemical burn mice model

Methods
We created ocular chemical burn models with 8-week-old BALB/c mice (n=45) by applying 0.1M sodium hydroxide(NaOH); the mice were then treated with 8-oxo-dG eye drops 10 mg/ml, 0.1% fluorometholone ophthalmic suspension, and phosphate buffered saline (PBS) twice daily. After seven days, clinical findings such as corneal integrity, clarity, and neovascularization were assessed. Histology, immunohistochemistry, inflammatory cytokine levels using real time polymerase chain reactions (PCRs), and amount of total reactive oxygen species in the corneas of the mice were also compared.

Results
Topical application of 8-oxo-dG and steroid resulted in a significant improvement of epithelial defects and clarity, compared to PBS (each p&lt;0.05). Stromal thickness in cornea was also decreased in the 8-oxo-dG and steroid treated mice, compared to PBS-treated controls. (p&lt;0.001) The expressions of F4/80 and neutrophil elastase-positive inflammatory cells in the stroma, and IL-1β and IL-6 cytokine levels in whole cornea were significantly reduced in the 8-oxo-dG group, compared to PBS group (each p&lt;0.05).

Conclusion
In the ocular chemical burn experimental model, topical 8-oxo-dG showed excellent anti-inflammatory effects those were not inferior than topical steroids.
Low dose interleukin-2 decreases P-glycoprotein activity and exerts synergistic anti-inflammatory effects with immunosuppressants in the treatment of lupus nephritis with steroid and immunosuppressive drug resistance
Authors: Wang Meiying , Hu Yiping , Yu Shengyan , Wang Qingwen , Singh Ram Raj 
Published: January 2023

Abstract

Objective
P-glycoprotein (P-gp) is capable of transporting glucocorticoids and immunosuppressants out of lymphocytes, resulting in drug resistance in lupus nephritis (LN). IL-2 decreases P-gp expression in cultured cells from human colon carcinoma. Here, we investigated the effects of low-dose IL-2 on the functionality of P-gp in PBMCs of steroid resistant LN patients and in kidneys in MRL/lpr mice.

Methods
30 drug resistant LN patients were treated with glucocorticoids and immunosuppressants with or without low-dose IL-2 for 12 weeks. Serum and urine collected before and after treatment were analyzed for anti-dsDNA, C3, C4, renal and liver function. P-gp expression and activity were detected in PBMCs by flow cytometry and rhodamine 123. MRL/lpr mice were treated with methylprednisolone (MP) with or without IL-2 for 4 weeks. Pathological changes as well as protein and mRNA expression of P-gp were assessed in kidneys.

Results
Compared to patients without IL-2 treatment, the patients treated with IL-2 had higher serum C3 (p=0.01) and C4 levels (p=0.04), while lower proteinuria(p=0.04), serum creatinine (p=0.03), anti-dsDNA levels (p&lt; 0.001), and accordingly lower SLEDAI (p=0.03). These modifications were associated with reduced P-gp expression (p&lt; 0.01) and activity (p=0.02) in PBMCs. Moreover, compared with controls, MRL/lpr mice treated with IL-2 and MP showed reduced proteinuria (p=0.002) and fewer acute and chronic renal pathological lesions. IL-2 attenuated renal deposition of IgG/C3, decreased renal expression of P-gp.

Conclusion
Low-dose IL-2 decreases P-gp activity and exerts synergistic anti-inflammatory effects with immunosuppressants in the treatment of LN with steroid and immunosuppressants resistance.