bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epithelial membrane protein 2 regulates transepithelial migration of neutrophils into the inflamed airspace
Authors: Lin Wan-Chi , Gowdy Kymberly , Madenspacher Jennifer , Zemans Rachel , Yamamoto Kazuko , Lyons-Cohen Miranda , Nakano Hideki , Janardhan Kyathanahalli , Williams Carmen , Cook Donald , Mizgerd Joseph , Fessler Michael 
Published: January 2023

Abstract
Neutrophil (PMN) migration from the circulation to the airway lumen is critical for pulmonary host defense but also causes bystander tissue injury that underlies a wide array of acute and chronic lung diseases. Whereas good evidence supports a role for intestinal epithelial cells in control of transmigration of extravasated PMNs into the intestinal lumen, little is known about whether and how respiratory epithelial cells regulate PMN influx into the airspace. Here, we identify epithelial membrane protein 2 (EMP2), a tetraspan membrane protein highly expressed in alveolar epithelial type 1 (AT1) cells but of unknown function in lung biology, as a master regulator of the terminal entry of PMNs into the airspace. EMP2−/− mice had reduced PMN influx into the airspace after multiple inhaled exposures and as a result exhibited attenuated lung injury and improved survival during bacterial pneumonia. Bone marrow chimeras, intravital PMN labelling, and in vitro assays suggest epithelial dysfunction in EMP2−/− lungs was responsible for deficient transepithelial PMN transit into airspace. We provide evidence that EMP2 supports epithelial surface display of multiple adhesion molecules that are required for cognate interactions with migrating PMNs and that it does so through suppression of epithelial caveolins. Moreover, EMP2 supports epithelial lipid raft mass in a manner dependent on putative cholesterol-binding motifs in its sequence. Taken together, we propose that EMP2-dependent membrane organization ensures proper display on AT1 cells of a suite of proteins required to instruct paracellular PMN traffic into the alveolus. Our findings identify EMP2 as a potential target for treatment of neutrophilic lung diseases.
Type1 IFN signaling on Tregs modulates the migration of Myeloid Derived Suppressor Cells
Authors: Tanwar Shalini , Metidji Amina , Shevach Ethan M 
Published: January 2023

Abstract
Multiple sclerosis is an autoimmune disorder whose severity is reduced with immune suppressive drugs. Therapeutic intervention with interferon-beta reduces disease exacerbations and delays relapses. The receptor for type 1 interferon, IFNAR, is present on virtually all cell types making it difficult to dissect the mechanisms involved. To address this issue, we induced experimental autoimmune encephalomyelitis (EAE) in mice with a conditional deletion (cKO) of IFNAR in T regulatory (Treg) cells (IFNARfl/flxFoxp3YFP-Cre). cKO mice developed severe EAE with an earlier onset than control mice. Although Treg cells from cKO mice appeared to be more activated, the activation status of and effector cytokine production by CD4+T cells in the draining lymph nodes (dLN) was similar in WT and cKO mice during the priming phase, but higher in cKO CD4+T cells in the effector phase. Interestingly, we noted a substantial reduction of myeloid derived suppressor cells (MDSCs) in the dLN of cKO mice, while generation of MDSCs in bone marrow and recruitment to spleen of WT and cKO mice were comparable. Surprisingly, we noted a decrease in the production of monocyte and granulocyte cell recruiting chemokine ligands by CD4+ and CD8+ T cells, B cells and endothelial cells in the dLN during the priming phase in the cKO mice. While modulation of Treg cell number and function by MDSCs has been documented, this study is one of the first to demonstrate that Treg cells modify the lymph node microenvironment by modulating MDSC homing and raises the possibility of a novel role for Treg cells in regulating the kinetics of MDSC recruitment during inflammatory conditions.
This research was supported by the Intramural Research Program of NIAID, NIH.
Limited recirculation of cytotoxic NK cells during normal homeostasis in humans
Authors: Hertwig Laura , Buggert Marcus , Knox James J. , Nguyen Son , Sparrelid Ernesto , Ivarsson Martin A. , Wedemeyer Heiner , Dori Yoav , Itkin Max G. , Betts Michael R , Björkström Niklas K. 
Published: January 2023

Abstract
Natural killer (NK) cells are well known for their cytolytic functions to directly kill virus-infected and malignant cells. Two major NK cell populations exist in humans: Cytotoxic CD56dim and immunoregulatory CD56bright NK cells. Although NK cells are distributed throughout the human body, little is known about which NK cell populations that traffic tissues and egress from tissues to recirculate back to blood. Here, we set outto determine the recirculation patterns of human NK cell subsets during normal homeostasis through access to multiple types of tissues, blood, and thoracic duct lymph (TDL). Whereas cytotoxic NK cells were dominant in peripheral blood, non-lymphoid tissues (liver, uterus, duodenum, adipose tissue) were enriched for immunoregulatory NK cells expressing markers of tissue-residency. Similarly, few cytotoxic NK cells were present in secondary lymphoid organs and efferent lymph (TDL). Instead, afferent and efferent venous blood of human liver was similar in NK cell subset composition as peripheral blood, suggesting that cytotoxic NK cells are retained in vasculature during steady-state. Ongoing mechanistic efforts include assessment of NK cell subsets in patients before and after blocking cellular egress from tissues with FTY-720 (S1PR agonist) treatment. These results offer a revised model for NK cell subset trafficking behavior and suggests that cytotoxic NK cells have limited access to peripheral tissues during normal homeostasis.
TNF targeting small molecule attenuates colonic inflammation in acute DSS-induced colitis mice
Authors: CHO OKKI , Jeong Young-Jin , Heo Tae-Hwe 
Published: January 2023

Abstract

Background
Inflammatory bowel disease (IBD) is a chronic and multifactorial inflammatory disorder which is comprising Crohn’s disease (CD) and ulcerative colitis (UC). Although the incidence of IBD has steady increase in worldwide, the conventional drug therapies with 5-aminosalicylates, corticosteroids, and immunosuppressants are insufficient to maintain remission and can occur side effects. Therefore, other class of drug therapies using specific cytokine inhibitor have recently been focused. In this study, we aimed to investigate that anti-inflammatory effects of TNF targeting small molecule in dextran sodium sulfate (DSS)-induced colitis model.

Methods
C57BL/6 (21–23g) mice were administered 2–2.5% DSS in the drinking water for 5 days to induce acute colitis. Different doses of IA-14069 (20, 40, 80, 160 mg/kg) were orally treated daily for 5–12 days and the mice were sacrificed for the experiments. Normal or DSS control group was given drinking water only or DSS only. Disease severity, body weight change, and colon length were measured, and serum levels of TNF, IFN-g, IL-6, IL-17 and IL-5 were analyzed by ELISA. Colonic epithelial damage was observed by H&E staining of colon tissue.

Results
Compared with normal group, oral administration of 80 mg/kg IA-14069 significantly inhibited the severity of colitis, loss of body weight, and colon shortening of the DSS-induced colitis mice. Moreover, mucosal damages and production of the proinflammatory cytokines were markedly suppressed by treatment of IA-14069.

Conclusion
These findings suggest that IA-14069, a TNF-targeting small molecule, exerts a suppressive effect on DSS-induced colitis and may be used as an IBD therapeutic agent.
Inhibition of ubiquitin-specific processing proteases 10 and 13 modulates IL-10 and TNF-α production in response to LPS in murine macrophages
Authors: Shah Pranav M , Talwar Harvinder , Samavati Lobelia 
Published: January 2023

Abstract
Innate immune response is activated by pathogen-associated molecular patterns (PAMPs) through Toll-like receptors (TLRs). To maintain immune homeostasis, TLR signaling molecules are regulated by a dynamic interplay of various ubiquitination (Ub) and deubiquitylation (DUB) events. Specifically, Lys-63 (K63)-linked ubiquitination on TRAF6 is involved in phosphorylation and activation of downstream MAPKs and IkB kinases. While certain types of ubiquitin modifications lead to activation and stability of proteins, other types cause increased proteasomal degradation and hence deactivation. DUBs are a class of the family of proteases that remove ubiquitin or ubiquitin-like proteins from a variety of protein-substrates. The role of DUBs in regulating the TLR pathway has not been well studied. Through RNA sequencing, we identified that LPS activation of bone marrow derived murine macrophages (BMDMs) leads to significant increase of two DUBs: ubiquitin-specific protease (USP) 10 and 13. To further study their role, we used Spautin-1, an inhibitor of USP10 and USP13. Spautin-1 modulated the LPS-mediated cytokine production and led to upregulation of IL-10, reduction of TNF-α, and had no effect on IL-6 production. However, we found no changes in expression of TRAF-6 or downstream MAPKs, including ERK, JNK, and P38. Alternative pathways were also studied with no effect in pSTAT-1, pSTAT-3, or A20 expression. Altered expression of pro-inflammatory mediators in the presence of Spautin-1 may have clinical importance associated with processes such as acute or chronic inflammatory processes.
Ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 inhibits IL-6 production by regulating Nur77 stability
Authors: Baek Suk-Hwan , Pei Han Zhong 
Published: January 2023

Abstract
Nur77 (NR4A1) plays an important role in various cellular responses such as apoptosis and inflammation. Nur77 is rapidly degraded in cells and its protein level is critically controlled. Although few ubiquitin E3 ligases regulating the Nur77 protein have been defined, the deubiquitinase (DUB) responsible for Nur77 stability has not been reported to date. We identified ovarian tumor domain-containing ubiquitin aldehyde binding protein 1 (OTUB1) as a DUB that stabilizes Nur77 by preventing its proteasomal degradation. We found that OTUB1 interacted with Nur77 to deubiquitinate it, thereby stabilizing Nur77 in an Asp88-dependent manner. This suggests that OTUB1 targets Nur77 for deubiquitination via a non-canonical mechanism. Moreover, we confirmed that OTUB1 reverses ubiquitination of the K48-linked chains in Nur77. Functionally, OTUB1 inhibited TNFα-induced IL-6 production by promoting Nur77 protein stability. OTUB1 modulated the stability of Nur77 as a counterpart of tripartite motif 13 (Trim13). That is, OTUB1 reduced the ubiquitination and degradation of Nur77 potentiated by Trim13. In addition, this DUB also inhibited IL-6 production, which was further amplified by Trim13 in TNFα-induced IL-6 production. These findings suggest that OTUB1 is an important regulator of Nur77 stability and plays a role in controlling the inflammatory response.
Modulation of Id3 induces a fetal-specific HEB-dependent gamma delta T cell developmental pathway in the adult mouse thymus
Authors: Selvaratnam Johanna Samantha , Anderson Michele K 
Published: January 2023

Abstract
Gamma delta T cells (γδ T cells) are key players in tissue barrier homeostasis and immunity. Understanding the molecular mechanisms by which γδ T cells are programmed to develop into the γδT17 lineage is essential to develop strategies for controlling IL-17 activity during pathogenic conditions. Previously we showed that the E protein transcription factor HEB is an essential regulator of the γδT17 lineage, and that the generation of fetal γδT17 cells occurs through a HEB-dependent fetal-restricted pathway that does not involve upregulation of CD73 (Pathway 2). Id3, an antagonist of E proteins, inhibits key regulators of γδT17 development. Therefore, we hypothesized that the loss of Id3 would enhance γδT17 development. We characterized adult Id3-RFP knock-in mice, and found that the Id3−/− recapitulated the previously established expansion of Vγ1+ γδ T cells. However, the adult Id3+/− thymus showed a re-emergence of Pathway 2, suggesting that reduced Id3 levels promotes the fetal HEB-dependent γδT17 program. Moreover, there was an increase in Vγ1-Vγ4- γδ T cells, which suggests the appearance of Vγ6+ cells that are normally restricted to the fetal thymus. Interestingly, Vγ4+ cells and Vγ1-Vγ4-cells in Id3+/− mice displayed Pathway 2 profiles, while Vγ1+ cells exhibited the normal adult thymic developmental profile leading to mature CD73+ γδ T cells in both Id3+/− and Id3−/− mice. Future studies will examine whether reduced HEB in the Id3+/− mice inhibits Pathway 2 in the adult thymus, and obtain more definitive evidence as to whether the Id3+/− γδ T cells in the adult thymus develop toward the IL-17 fate. In conclusion, our studies indicate that the balance between E proteins and Id3 regulates the developmental programming pathway of γδ T cells.
A critical role for the Slam/SAP signaling pathway in the developmental programming of γδ T cell function
Authors: Boyson Jonathan E , DeVault Victoria L , Mistri Somen K , Mei Linda , Musial Shawn C , Spear Camarie , Dragon Julie A. , Veillette Andre , Dienz Oliver 
Published: January 2023

Abstract
Tissue-resident γδ T cells constitute a prominent source of IL-17 and IFN-γ in mucosal tissues where they provide an important first line of defense against pathogens. Unlike conventional αβ T cells, most γδ T cells are programmed during thymic development to produce either IFN-γ or IL-17. The mechanisms, however, that direct γδ T cell functional programming in the thymus remain unclear. Slam receptors are a family of nine (SLAMf1 to SLAMf9) cell surface receptors that are expressed only on hematopoietic cells and which play a central role in the host immune response. Most Slam receptors transduce signals via the small adapter protein SAP, and mice deficient in SAP exhibit numerous immunological defects. Relatively little is known, however, of the function of this signaling pathway in γδ T cells. Here, we report that distinct Slam receptor expression profiles mark functional γδ T cell subsets. Whereas SLAMf1 expression was associated with IL-17-producing CD27− RORγt+ γδ T cells, SLAMf6 expression was associated with IFNγ-producing CD27+ cells. We found that Slam receptor expression profiles were established on discrete thymic γδ T cell subsets as early as embryonic day 17 (E.17), as was the association of SLAMf1 with RORγt expression. Disruption of Slam receptor signaling by deletion of SAP resulted in a significant loss of E.17 thymic CD44hiRORγt+ γδ T cells, and a significant shift in the ratio of IFN-γ/IL-17-producing γδ T cells in both thymus and peripheral tissues. These results demonstrate for the first time that the Slam/SAP signaling pathway plays a significant role in the functional programming that regulates the γδ T cell IFN-γ/IL-17 axis during thymic development.
Conditional deletion of the V-ATPase a2-subunit disrupts intrathymic T cell development
Authors: Peterson Theodore V , Reynolds Joseph M 
Published: January 2023

Abstract
Proper orchestration of T lymphocyte development is critical, as T cells underlie nearly all responses of the adaptive immune system. Developing thymocytes differentiate in response to environmental cues carried from cell surface receptors to the nucleus, shaping a distinct transcriptional program that defines their developmental outcome. Our recent work has identified a previously undescribed role for the vacuolar ATPase (V-ATPase) in facilitating the development of murine thymocytes progressing toward the CD4+ and CD8+ αβ T cell lineages. Vav-Cre recombinase-mediated deletion of the a2 isoform of the V-ATPase (a2V) in mouse hematopoietic cells leads to a specific and profound loss of peripheral CD4+ and CD8+ αβ T cells. Utilizing T cell-restricted Lck- and CD4-Cre strains, we further traced this deficiency to the thymus and found that a2V plays a cell-intrinsic role throughout intrathymic development. Loss of a2V manifests as a partial obstruction in the double negative stage of T cell development, and later, a near complete failure of positive selection. These data deepen our understanding of the biological mechanisms that orchestrate T cell development, and lend credence to the recent focus on V-ATPase as a potential chemotherapeutic target to combat proliferative potential in T cell lymphoblastic leukemias and autoimmune disease.
STAT5b dimers and tetramers are critical for Mast Cell Function
Authors: Kiwanuka Kasalina N , Lin Jianxin , Leonard Warren J , Ryan John J 
Published: January 2023

Abstract
Signal transducers and activators of transcription (STATs) are latent transcription factors vital for lymphoid, myeloid, and erythroid cell development, survival, proliferation, and function. Activated STATs form dimers that translocate to the nucleus and bind high affinity STAT DNA motifs to modulate gene expression. We previously found that Stat5b is required for IgE-mediated mast cell cytokine production in vitro. In this study, we found that STAT5b KO mice demonstrate decreased sensitivity to IgE-mediated passive systemic anaphylaxis (PSA) and reduced cytokine production in vivo. This is not due to differences in mast cell numbers or distribution. Interestingly, STAT5b KO mice exhibit elevated levels of serum IgE that could diminish PSA by preventing binding of antigen-specific IgE. Increased serum IgE is not tied to changes in B cell number or their ability to produce IgE in vitro. In addition to dimers, activated STAT proteins can also form tetramers through an oligomerization process once dimers bind to tandem low-affinity STAT DNA motifs. Similar to STAT5bKO, in vitro IgE-mediated cytokine production is decreased in Stat5a-Stat5b double knock-in (DKI) mice in which STAT5 proteins can form dimers but not tetramers. In vivo, DKI mice exhibit decreased PSA sensitivity, with no difference in mast cell numbers or distribution, and a modest increase in serum IgE. Collectively, these data illuminate the unique and specific roles of STAT5 dimers and tetramers in mast cell function and allergic disease.
Transient Suppression and Functional Modulation of Mucosal Mast Cells for the Treatment of Allergic Disease
Authors: Kurashima Yosuke , Takasato Yoshihiro , Kiuchi Masahiro , Hirahara Kiyoshi , Murasaki Sayuri , Kunisawa Jun , Kubo Masato , Nakayama Toshinori , Kiyono Hiroshi 
Published: January 2023

Abstract
Food allergy is estimated to affect about 5 percent in children and adults and causes life-threatening reactions. Especially food allergy in infant and child shows severe gastrointestinal symptoms, including diarrhea, vomiting, and abdominal pain. To control the food allergy, allergen desensitization by oral immunotherapy (OIT), has been shown to an effective therapeutic approach; however, limited information is currently available for basic understandings of OIT induced immunological events at intestinal mucosa. In this study, we found that orally desensitized intestinal mast cells acquired the regulatory function for the inhibition of food allergic response. Indeed, the gene analysis showed the increase of regulatory cytokine IL-2 and IL-10 expressions in orally-desensitized intestinal mast cells; on the contrary, decreased Th2 cytokine expressions were suppressed by epigenetic control. Thereby, mice depleting these regulatory mast cells during OIT led to the reduction of functional regulatory T cell-mediated inhibition of allergic responses. These findings newly uncovered characteristics desensitized mast cells to acquire regulatory suppressive milieu in the allergic disease mucosa and indicated the novel roles of mast cells in the effective anti-allergic therapy.
Pre-treatment with lipopolysaccharide (LPS) protects against a normally lethal respiratory viral infection
Authors: Resiliac Jenny , Rohlfing Michelle , Santoro Jennifer , Hussain Syed-Rehan A. , Grayson Mitchell H 
Published: January 2023

Abstract

Rationale
Severe respiratory viral infections are responsible for significant morbidity and mortality in the young and elderly. The mechanism of the mortality is not known. We hypothesized that impaired neutrophil (PMN) function might contribute. To test this, we used the Sendai virus (SeV, murine parainfluenza virus type 1) mouse model, and examined the effect in mice with deficient PMN responses (Mpo−/−). Since lipopolysaccharide (LPS) exposure leads to accumulation of PMN, we tested the effect of LPS on mortality. Because the SeV model depends on production of IgE against the virus, we used Ige−/− mice to examine whether IgE could be playing a role in development of mortality.

Methods
C57BL6 wild-type (WT) mice were intranasally (i.n.) inoculated with 2×106 pfu SeV (lethal dose) alone or given 3μg LPS i.n. 24 hours before or after SeV and survival determined. Similar experiments were performed with mice deficient in myeloperoxidase (Mpo−/−) or IgE (Ige−/−).

Results
Regardless of genetic background, all mice infected with SeV or given LPS after SeV died by day 12 post SeV. However, LPS given before SeV led to 25% survival in WT mice, compared with 88% survival of Ige−/− mice and 100% survival of Mpo−/− mice (p=0.0134 for all 3 groups, Mantel-Cox, n≥4).

Conclusion
LPS pretreatment provides protection from a lethal dose of SeV, but only when PMN function or IgE is deficient. Thus, PMN and IgE appear to be important for development of respiratory viral infection mortality. We are actively exploring how LPS provides protection, and the mechanism(s) underlying the PMN and IgE requirement for viral induced mortality.
Probiotic Lactobacillus GG attenuates pulmonary inflammation through interfering the crosstalk between intestinal microbiota and ILC2 in asthmatic mice
Authors: Peng Guiying , Liu Zirui , Wang Yongan , Ge Dongyu , Hao Yu 
Published: January 2023

Abstract
Type 2 innate lymphoid cells and microbiota play crucial roles in type 2 immune response which is associated with asthma. In this study, we applied an OVA-induced allergic asthma model to examine the treatment of LGG and antibiotics-induced microbiome depletion to analyze the relationship between the microbes and ILC2.
We found that pretreatment of LGG before sensitization in mice reduced the numbers of inflammatory cell from bronchoalveolar lavage fluid, inhibited the levels of IL-5 and IL-13 and ameliorated pulmonary inflammation as well as mucus secretion. Additionally, LGG significantly inhibited the induction of KLRG1+ILC2. 16SrDNA sequencing results indicated that asthmatic mice had a lower gut microbiome diversity and abundance compared with control mice. While LGG treatment improved microbial diversity. Notably, inflammatory cells were significantly decreased in different regions of jejunum, ileum and colon in LGG treated asthmatic mice.
On the other hand, depletion of intestinal microbiota with antibiotics obviously increased the number of KLRG1+ILC2 from intestinal lamina propria and induced the mucus hypersecretion in the lower respiratory tract. Moreover, intestinal microbial depletion strengthened the pulmonary inflammatory and induction of KLRG1+ILC2 in asthmatic mice. Furthermore, pretreatment of LGG didn’t inhibit the pulmonary inflammation in asthmatic mice with depletion of intestinal microbiota.
These findings uncovered a close crosstalk between ILC2 and pulmonary inflammatory, suggesting intestinal microbiota might be a primary determinant for the development of asthma, thus provided additional evidence for the strain treatment on allergic asthma in the future.