bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microbiota upregulate distinct APC functions in each intestinal dendritic cell subset, in a Myd88-independent fashion
Authors: Hammer Gianna , Liang Jie , Huang Hsin-I , Benzatti Fernanda , Karlsson Amelia , Hale Laura P. 
Published: January 2023

Abstract
While dendritic cells (DCs) are known to control T cell responses to pathogens, how dynamics between DCs and microbiota impact mucosal T cells is poorly defined. To understand how microbiota impact APC functions of intestinal DCs, we use DCs lacking A20, a signaling attenuator, to amplify DC responses to microbiota. We find each intestinal DC subset possesses unique APC functions that enforces strict subset-specific rules to DC-instruction of either IFNg+ or IL-17+ T cells. While CD103+ CD11b− DCs have potent abilities to instruct IFNg+ T cells, these DCs do not induce IL-17+ T cells. In mirror image, CD103+ CD11b+ DCs induce robust numbers of IL-17+ T cells, but induce no IFNg+ T cells. By contrast, CD103− CD11b+ DCs possess dual abilities to instruct IFNg+ and IL-17+ T cells. Interestingly, distinct mechanisms govern IFNg- and IL-17-inducing APC functions of intestinal DCs: While CD80/86 is required for DC-instruction of IFNg+ T cells, DC-instruction of IL-17+ T cells requires IL-6. We further show that MyD88, although notorious in ability to upregulate APC functions, are not required to upregulate APC functions of intestinal CD103+ DCs. In support of this, we find that mice with DC specific loss of both A20 and MyD88 spontaneously develop inflammation of small intestine. Finally, we ablate CD103− CD11b+ DCs and CD103+ CD11b+ DCs and find that these DCs are required for expansion of pathological Th17 cells. These results suggest that microbiota trigger distinct APC functions in different DC subsets and that in the context of intestinal inflammation and disease, there are defined teacher-student relationships between specific DC subsets and specific mucosal T cells.
TLR10 is a Negative Regulator of Human Monocyte Innate Immune Responses
Authors: Hess Nicholas J , Felicelli Christopher , Grage Jennifer , Mercado Reinaldo , Tapping Richard I. 
Published: January 2023

Abstract
Toll-like receptors (TLRs) are important pattern recognition receptors involved in the activation of innate immune responses against foreign pathogens. Humans possess ten TLRs, of which TLR10 is the only remaining TLR without a known ligand, signaling pathway or cellular function. Recent data by our lab has shown for the first time a suppression of cellular innate immune responses in primary human monocytes that is mediated by a TLR10 monoclonal antibody. This study sought to expand on our initial observations by investigating the signaling pathways, gene expression and long-term consequences of TLR10 engagement on primary human monocytes. Our data shows that TLR10 engagement is sufficient to suppress both IL-6 and TNF-α induction in response to TLR4, TLR7/8 or CD40 stimulation. Cellular lysates show that the primary target of TLR10 signaling may be to inhibit phosphorylation of Akt and its downstream targets. To further this hypothesis, we have performed RNA sequencing on cellular extracts to determine which pathways are targeted by TLR10 signaling. Our data also suggests that these events also affect long-term differentiation of monocytes into macrophages and dendritic cells. Macrophages and dendritic cells differentiated in the presence of a TLR10 antibody exhibit suppressed differentiation markers such as CD80/CD86 and HLA-DR/CD16 respectively after four days of differentiation. These data show that TLR10 is a novel regulator of innate immune responses on primary human monocytes and may have eventual therapeutics benefits in chronic inflammatory and auto-immune diseases.
Comparative proteomic analysis of chicken macrophages stimulated with Salmonella Lipopolysaccharide (LPS) and Monosodium Urate (MSU) Crystals
Authors: Makkar Sarbjeet K , Liyanage Rohana , lay jackson o , RATH NARAYAN C 
Published: January 2023

Abstract
Immune system cells are armed with recognition receptors by means of which they can sense pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs). Interaction of pathogen as well as damage associated ligands with their cognate receptors drives transcriptional and translational changes. To study the proteomic differences between signal transduction pathways involved in microbial induced and sterile injury, we used chicken macrophages HTC as a model system. Cells were labeled and treated with LPS or MSU by using SILAC proteomic approach. After 20 hrs of stimulation, the protein was extracted from secretome and cell lysate, quantified and subjected to in-solution digestion followed by liquid chromatography/tandem mass spectrometry. We quantified 150 proteins using Skyline software, 30 were upregulated and 18 down regulated in LPS treated cells and 40 upregulated and 11 down regulated in MSU treated cells. Interleukin 8, a secretory protein is differentially upregulated in LPS group. Cathepsin K, vimentin, kinases are some of the significantly upregulated cell lysate proteins in LPS group. Lactate dehydrogenase, heat shock, microtubule, annexin are significantly upregulated in MSU stimulated cell lysate. Functional annotation of proteins in both the groups by gene ontology software shows most of the proteins are involved in cytoskeleton remodeling, cell migration and cell signaling, which may be important in immune activation except nucleic acid binding transcription activity factor proteins which are uniquely expressed in LPS group. In conclusion our study gives an insight about the functional differences between pathogen and sterile associated inflammation at cellular level.
Different characteristics of Myeloid-derived suppressor cells from septic and tumor-bearing mice
Authors: Shu Qiang , Qin Chaojin 
Published: January 2023

Abstract

Background
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid progenitor cells and immature myeloid cells. These cells have immunosuppressive properties and express myeloid differentiation markers Gr-1 and CD11b in mice. The characteristics of MDSCs in different pathological conditions remain unclear.

Methods
Polymicrobial sepsis was induced by cecal ligation and puncture. For tumor model, mice were injected s.c. in the flank with 5×105 3LL or B16 tumor cells. Splenic Gr-1+ CD11b+ MDSCs were harvested from 7-day septic mice and three-week tumor-bearing mice, which purified using magnetically assisted cell sorting.

Results
MDSCs from tumor (3LL and B16)-bearing and septic mice shared a common phenotype and morphology. In contrast to tumor-bearing MDSCs, septic MDSCs were mainly characterized as neutrophil like-MDSCs, which expressed lower levels of CD115. Tumor bearing MDSCs have a greater inhibitory effect on Ag-induced CD4+ T cell proliferation than those from septic mice, and expressed higher levels of ARG-1. In addition, septic MDSCs significantly induced macrophage to M1 (F4/80+ CD206−) and expressed proinflamatory cytokine IL-6, whereas tumor-bearing MDSCs induced macrophage to M2 (F4/80+ CD206+) and expressed anti-inflammatory cytokine TGF-beta.

Conclusion
Sepsis derived MDSCs are functionally different from tumor-bearing MDSCs, which suggests there different functions in the disease’s progress.
Notch-1 regulation of microRNAs alter the expression of proinflammatory cytokines and Th1 response
Authors: Chandiran Karthik , Minter Lisa M 
Published: January 2023

Abstract
Notch signaling is required for activation and differentiation of T cells. Upon its S3 cleavage by gamma secretase, Notch intracellular domain triggers the expression of various molecules depending on its binding partners. The data published from our lab states that Notch1 can induce Th1 immune response and regulates the expression of IFNγ by modulating the expression of the transcription factor T-bet. However the detailed mechanism behind Notch1 mediated Th1 differentiation is not clear. Here we report that Notch1 can regulate Th1 differentiation by targeting microRNAs. miR-29 is a family of micro RNAs (miR29a,b,c) that targets ifng and both its transcription factors tbx21 and eomes directly by binding to their respective 3′ UTRs. By using novel gamma secretase inhibitors (GSIs) we show that Notch can modulate the expression of miR-29. Overexpression of Notch1 in T cell hybridoma cell lines further validates Notch1- mediated mirR-29 regulation. These results indicate a novel regulatory mechanism of T cell differentiation through Notch1 mediated microRNA expression.
Short-chain fatty acid HDAC inhibitor-mediated downregulation of AID expression and class switch DNA recombination is relieved by estrogen through modulation of selected microRNAs
Authors: shen Tian , Sanchez Helia Nasrollahi , Zan Hong , Casali Paolo 
Published: January 2023

Abstract
Estrogen contributes to the elevated antibody response to vaccines in women and the female bias of autoimmune responses, likely by increasing class-switched and hypermutated antibodies and pathogenic autoantibodies. As we have shown, estrogen potentiates the induction of AID, which is critical for class switch DNA recombination (CSR) and somatic hypermutation (SHM), through upregulation of HoxC4. Estrogen may also alter AID gene expression through epigenetic modifications. As we have also shown, short-chain fatty acid (SCFA) histone deacetylase inhibitors (HDIs), including valproic acid and butyrate, upregulated miRNAs that silence AID expression, resulted in reduction of T-dependent and T-independent antibody responses in C57BL/6 mice and autoantibody responses in lupus-prone mice. Here we found that the HDI-mediated downregulation of antibody and autoantibody responses was reversed by estrogen but significantly enhanced by deletion or inhibition of estrogen receptor α (ERα). In B cells, estrogen downregulated the expression of miR-26a, which we found to target the 3′UTR Aicda mRNA. miR-26a was highly expressed in activated B cells and significantly upregulated by SCFA HDIs. Estrogen enhanced cytoplasm to nuclear translocation of HDAC4/HDAC5, and decreased histone acetylation of the host gene of miR-26, and possibly, other selective miRNAs. Finally, The estrogen-mediated enhancement of AID was abrogated by selective inhibition of HDAC4/HDAC5 by LMK258, which decreased CSR. Collectively, our findings provide mechanistic insights into the immunomodulating activity of estrogen and its potential use as therapeutic target in systemic autoimmunity.
Supported by the NIH grants AI 105813, AI 079705.
IL-10-induced miR-155 targets SOCS1 to enhance IgE-mediated mast cell function
Authors: Qayum Amina Abdul , Paranjape Anuya R , Abebayehu Daniel , Kolawole Elizabeth Motunrayo , Haque Tamara , McLeod Jamie J , Spence Andrew J , Caslin Heather , Chumanevich Alena P , Baker Bianca , Taruselli Marcela T , Oskeritzian Carole A , Ryan John J 
Published: January 2023

Abstract
Interleukin 10 (IL-10) is an important regulatory cytokine that modulates a wide range of immune cells. While it is best known for its ability to suppress inflammation, IL-10 has been found to be pathogenic in several human and animal studies of inflammatory diseases. There is a considerable gap in our understanding of the molecular mechanisms behind the pro-inflammatory effects of IL-10. Long term (3–4 day) IL-10 treatment has been shown to suppress mast cell function. In this study we report the effect of short-term (24 hour) IL-10 treatment, which enhanced IgE-mediated histamine and cytokine production both in vitro and in vivo. This pro-inflammatory effect was consistent in mouse and human skin mast cells. IL-10 enhanced activation of the key FcɛRI signaling proteins Stat5, JNK, and ERK. We demonstrate that IL-10 effects are dependent on Stat3 activation, eliciting miR-155 expression, with a resulting loss of SOCS-1. The importance of miR-155 was demonstrated by the inability of IL-10 to enhance anaphylaxis in miR-155-deficient mice. Taken together, our results reveal an IL-10-induced, Stat3-miR-155 signaling pathway that can promote mast cell inflammatory responses.
Short-chain fatty acid (SCFA) histone deacetylase inhibitors produced by gut microbiota regulate selected microRNAs to modulate local and systemic antibody responses
Authors: Sanchez Helia N. , shen Tian , Taylor Julia Renee , Munoz Kristina , Zan Hong , Casali Paolo 
Published: January 2023

Abstract
Epigenetic marks and factors, such as histone modifications and miRNAs, interact with genetic programs to regulate intrinsic B cell functions and inform antibody responses. As shown by our transcriptome and miRNome analyses, histone deacetylase inhibitors (HDIs) selectively downregulate AID, which is critical for class switch DNA recombination (CSR) and somatic hypermutation (SHM), and Blimp-1, the master transcription factor for B cells differentiation to plasma cells, by selectively upregulating miRNAs that target Aicda and Prdm1 mRNAs. As we have also shown, HDI-mediated impairment of CSR, SHM and plasma cell differentiation blunted T-dependent and T-independent antibody responses in wild type mice and autoantibody responses in lupus-prone mice. Potent HDI activity is displayed by butyrate and propionate, two abundant SCFA molecules generated by gut microbiota through fermentation of dietary fibers. We found that these SCFAs synergistically downregulate AID and Blimp-1 expression through selective miRNA upregulation. Feeding a no-fiber diet, or decreasing the load of SCFA-producing microbiota by treating mice with vancomycin reduced gut and serum SCFAs and resulted in increased IgA and IgG1 titers in serum and feces, and IgA+, IgG1+ B cells and plasma cells in Peyer’s patches, mesenteric lymph nodes and spleen. This outcome was reversed by administration of butyrate and propionate, which also synergistically inhibited CSR to IgG and IgA in purified human and mouse B cells in a dose-dependent fashion. Thus, endogenous HDIs integrate cues from metabolites by gut microbiota and relay them to selective downstream effectors, e.g. miRNAs, thereby modulating B cell differentiation and antibody/autoantibody responses.
Elucidating the contribution of IRF3 to effector and memory cytotoxic T cell responses after influenza virus infection
Authors: Vogel Alexander J , Petro Thomas , Brown Deborah 
Published: January 2023

Abstract
The role of interferon regulatory factor (IRF) 3 in initiating the type I interferon response in innate immune cells has been well studied in the context of viral infection. However, it is less clear what impact IRF3 has in shaping and maintaining adaptive immune responses. Previous reports have demonstrated that when restimulated, both CD4 and CD8 T cells from IRF3 knockout (KO) mice have significantly reduced expression of Granzyme B 30 days after infection or following secondary influenza A virus (IAV) challenge. To determine whether deficiencies in Granzyme B correlate with CTL function, we are examining the cytotoxic potential and specific antiviral lytic activity after primary and secondary challenge with IAV in CD4 and CD8 cells. Additionally, as early signals derived from antigen presenting cells (APCs) influence effector and memory T cell development, the innate immune response following IAV infection was examined. Our results demonstrate the innate response is not compromised in IRF3 KO mice at day 1 or 3 post IAV infection in the draining lymph node. Interestingly, macrophages and dendritic cells had decreased expression of MHCII and CD86 at both time points in the lung. These results suggest that while initial priming is sufficient in the draining lymph nodes, secondary factors in the lung could provide T cells with the signals needed for effective memory development. Together, this work provides insight into the molecular regulation of T cell responses to viral infections and highlights the role IRFs play in the development of high quality effector and memory T cells.
The molecular basis of CD4+ T cell priming for CD8+ T cell memory formation
Authors: Cullen Jolie G , Olshansky Moshe , Turner Stephen 
Published: January 2023

Abstract
A long-lived pool of potent memory cells is the defining feature of adaptive immunity. Memory CD8 T cells offer protection for the life of the host due to their unique capabilities to survive in the absence of antigen and respond rapidly to secondary challenge. Therefore, effective CD8 T cell memory is the goal of cell-mediated vaccination strategies. While it is well established that CD4 help is required for CD8 T cell memory formation, it is unclear when during CD8 differentiation this help is required. Further, the affect that CD4 help has on the transcriptional profiles of CD8 T cells and the molecular pathways they use during the generation and maintenance of memory CD8 T cells remains elusive. Using a mouse model of Influenza A virus infection, where priming occurs in the presence or absence of CD4 T cell help, we have pinpointed that help is required during the initial priming of CD8 T cells, and not during memory maintenance or recall. Genome wide RNA-sequencing analysis of the transcriptional signatures between resting “helped” and “ unhelped” memory CD8 T cells reveals surprisingly few differentially expressed genes. However, upon reactivation, “helped” memory CD8 T cells exhibited greater transcriptional up regulation than their “unhelped” counterparts, and utilization of alternate molecular pathways. Our analysis revealed that CD4 help during initial priming is essential for establishing a memory cell pool with enhanced transcriptional potential. Intriguing metabolism differences are currently being further dissected based on this RNA-sequencing data. Thus, CD4 T cell dependent programming likely underpins rapid responsiveness, a key characteristic of memory CD8 T cells.
ent-kaur-16-en-19-oic acid protects mice from neutrophilic lung inflammation and sepsis
Authors: Joo Myungsoo , Kim Kyun Ha , Lee Ji-Yeon , Kwun Min Jung , Han Chang Woo , Choi Jun-Yong 
Published: January 2023

Abstract
The roots of Aralia continentalis Kitagawa (Araliaceae), a remedy to treat patients with inflammatory diseases in traditional Asian medicine, contain kaurenoic acid (ent-kaur-16-en-19-oic acid: KA) that activates Nrf2, a key transcription factor that suppresses inflammation. Here, we explored a possible therapeutic usage of KA against acute lung injury (ALI), a neutrophilic inflammatory lung disease. When administered intratracheally (i.t.) to mouse lungs 2 h after intraperitoneal lipopolysaccharide injection that induces lung inflammation, differential amounts of KA (0.3, 3, or 30 μg/kg) significantly suppressed cellular and neutrophil infiltrations and the expression of pro-inflammatory cytokines in mouse lungs. In a mouse model of sepsis, a major cause of ALI, single i.t. KA (3 μg/kg) administered 2 h after the onset of sepsis significantly decreased the mortality of the mice. KA treatment increased Nrf2-dependent gene expression in the lung. However, while KA could not significantly suppress cellular infiltration to the lung of Nrf2 knockout (KO) mice, KA suppressed neutrophil infiltration to the lung of Nrf2 KO mice, suggesting that Nrf2 is not prerequisite for KA to suppress neutrophil infiltration. Together, these results suggest that KA, likely via multiple pathways, exerts a suppressive effect against neutrophilic lung inflammation and sepsis in mice.
Phospholipase C mediates therapeutic effects of WKYMVm against sepsis
Authors: Kim Hyung Sik , Lee Sung Kyun , Park Min Young , Kim Ji Cheol , Bae Yoe-Sik 
Published: January 2023

Abstract
Sepsis is a serious life-threatening complicated clinical syndrome that results from a detrimental or damaging host reaction to infection. Previously we reported that an immune stimulating peptide, Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm), strongly induced therapeutic effects against polymicrobial sepsis via formyl peptide receptor 2. In this study, we investigated the mechanism involved in WKYMVm-induced anti-septic activity focusing on phospholipase C (PLC). WKYMVm strongly stimulated mouse neutrophils, resulting in calcium increase which was completely blocked by a PLC-selective inhibitor (U-73122). We found that PLC-specific inhibitor U-73122 markedly blocked therapeutic effects of WKYMVm against sepsis. WKYMVm-induced inhibition of lung inflammation and lymphocyte apoptosis in cecal ligation and puncture sepsis model were markedly blocked by U-73122. We also found that WKYMVm-stimulated bactericidal activity and neutrophil migration to event area were also strongly inhibited by the PLC-selective inhibitor (U-73122). Taken together, we suggest that PLC enzymatic activity is essentially required for the therapeutic activity of WKYMVm against sepsis.
TNF deficiency leads to splenomegaly during Cutaneous Leishmaniasis
Authors: Hu Shanshan , Marshall Cameron , Darby Jocelyn , Korner Heinrich , Lyons Bruce 
Published: January 2023

Abstract
Cutaneous leishmaniasis in resistant C57BL/6 (B6.WT) mice is resolved spontaneously by Th-1 mediated production of TNF-α and IFN-γ, with consequent induction of inducible nitric oxide synthase. Intriguingly, C57BL/6 mice with a TNF gene knockout (B6.TNF−/−) show uncontrolled fatal infection involving the liver and spleen, which are the two main targets in visceral leishmaniasis. The exact role of TNF or specific mechanism, which is responsible for the fatal outcome of Leishmania infection in this gene-deficient mouse strain, is not yet understood.
B6.TNF−/− mice spleen significantly enlarged from Day 28 post-infection, and they were more than 2-fold larger than B6.WT mice on Day 35 and Day 42. To confirm Leishmania infection in the spleen, limiting dilution assay was recruited and showed Leishmania existed since Day 21 in B6.TNF−/− mice, but there was none evident in B6.WT mice. Diff Quik stain results confirmed that architecture of spleen in B6.TNF−/− was disorganized and white and red pulps were no longer clearly separated. Cells infected with Leishmania were dispersed throughout the spleen and lymph cells infiltrated. A gradually increasing population CD45+CD11b+CD11chighCCR2+Ly6C+F4/80high was emerged in B6.TNF−/− mice, which had both dendritic cell and macrophages like phenotype. In vitro, at steady state, macrophages from B6.TNF−/− mice showed no difference comparing to B6.WT. After exposure with Leishmania promastigotes, they showed potential M2-like phenotype and more easily succumbed to infection
We are currently sorting this population from B6.TNF−/− mice and examining the characteristics and potential mechanisms that may affect the spleen immunity against Leishmania major infection in the absence of TNF.