bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of the misregulation of RhoA and RhoH in autoimmune mice. (HUM7P.302)
Authors: Antoni Angelika , Ray Chelsea , Kohn Ryan , Andreyko Diana , Levine Jerrold 
Published: January 2023

Abstract
When cultured in the presence of apoptotic cells, cell bodies or lipids, RhoA is misregulated in macrophages from all 6 autoimmune mouse strains but none of the 7 normal strains tested. Misregulation of RhoA results in defective morphology, altered cytokine production, and increased adhesion. The same macrophages cultured without apoptotic cell lipids had properly regulated RhoA and behaved normally. Normal mouse macrophages cultured with the Rho inhibitor C3 toxin, had defective macrophage morphology and behavior. Therefore, we proposed that autoimmunity is due to an apoptotic cell recognition signaling defect and that normal macrophage function may be restored by a chemical reversal of the defect. Our new data demonstrate that lupus strain, MRL, macrophages cultured in the presence of C3 no longer had defects in morphology and function. The fact that a RhoA inhibitor restored RhoA function indicates that the misregulation in autoimmune macrophages involves a RhoA regulator also affected by C3 and not RhoA itself. RhoH is a known inhibitor of RhoA and it is only expressed in hematopoietic cells. Experiments comparing RhoH expression in BALB and MRL macrophages suggest at least four different sizes of RhoH protein are expressed in normal macrophages in response to lipid exposure and that lupus macrophages do not express the multiple forms of RhoH even in the presence of lipids. A lack of proper RhoH expression could be behind the autoimmune macrophage defect.
TCR-independent activation of T-cells through CD31 triggering as an etiology of cytokine production in juvenile idiopathic arthritis (JIA). (HUM7P.311)
Authors: Ferguson Ian , Griffin Patricia , Michel Joshua , Kietz Daniel , Rosenkranz Margalit , Kietz Daniel , de Vallejo Abbe 
Published: January 2023

Abstract
Pro-inflammatory cytokines in the blood and synovium are key actors in JIA pathology. We recently reported that JIA patients have an over abundance of prematurely senescent CD8+ T cells expressing CD31, an adhesion molecule expressed by granulocytes and endothelial cells. CD31 triggering alone is sufficient to activate such senescent T cells. This study examined whether cytokine profile in JIA may be derived from T cell activation through CD31 ligation independent of the TCR. Results showed a cytokine signature of JIA characterized by dominance of IL-6, IL-10 and TNFα. Notably, patients with oligoarticular JIA showed higher levels of IFNγ and IL-17 family cytokines than those with polyarticular JIA. All patients also had a novel subset of T cells deficient in CD4, CD8, and CD28, but expressing CD31. Cross-linking bioassays, using anti-CD31 or its ligand CD38, show high levels of induction of IL-2, IL-17, and IFNγ. This CD31-driven, TCR-independent cytokine production was also verified by using somatic T cell line mutants that lack TCR and TCR/CD3, respectively, but both are CD31+. The observed cytokine production was associated with the phosphorylation of the signaling substrates ZAP70, cAbl, and p65-NFΚB. TCR independent, CD31-driven induction of these cytokines suggests maladaptive T cell function in JIA. Further investigation on the relevance of IFNγ and IL-17 to disease activity, and the CD31 signaling pathway may allow for innovations in immunotherapy.
BTLA expression on CD4+ T cells negatively regulates the development of pulmonary fibrosis (HUM7P.319)
Authors: Casaos Joshua , Takahashi Stephenie , Blaine Kelly , Hrusch Cara , Noth Imre , Sperling Anne 
Published: January 2023

Abstract
The role of the adaptive immune response in idiopathic pulmonary fibrosis (IPF) has been an area of debate. Several studies have shown that patients with IPF had increased numbers of T cells in their lungs, suggesting that these cells may play a role in disease pathogenesis. We have found that decreased expression of an important co-inhibitory molecule, B- and T- lymphocyte attenuator (BTLA) on peripheral blood CD4+ T cells is correlated with IPF patients most likely to rapidly progress in their disease course. Based on these findings, the objective of our study was to determine the role of BTLA on CD4+ T cells in the development of pulmonary fibrosis by utilizing a mouse model of bleomycin-induced pulmonary fibrosis. We found that, similar to our patient studies, bleomycin treated WT mice express decreased levels of BTLA on CD4+ T cells compared to untreated WT mice. BTLA-/- mice exhibited significantly increased weight loss and pulmonary fibrosis compared to WT mice. However, CD4+ depletion in the BTLA-/- mice prior to bleomycin challenge protected these mice, as they lost less weight had decreased lung collagen deposition. These findings support a significant role for the loss of BTLA on CD4+ T cells in the pathogenesis of fibrotic disease progression.
Transcriptomic signatures convergent across multiple studies of upper and lower airway allergic disease support the unified airway hypothesis (HUM7P.321)
Authors: Berdnikovs Sergejs , Schleimer Robert , Bryce Paul , Abdala-Valencia Hiam 
Published: January 2023

Abstract
Asthma is frequently associated with co-morbid diseases of the upper airways, including chronic rhinosinusitis (CRS). This has led to a hypothesis that the upper and lower airway may be immunologically linked, functioning as a continuous mucosal epithelial barrier interacting with the environment. Despite a growing number of transcriptomics studies, the differences and similarities between upper and lower airways in allergic disease are still poorly understood. We analyzed raw microarray data from three independent studies of CRS and four studies of asthma, and conducted a secondary multivariate and pathway analysis to identify genes commonly altered in both diseases. Despite regional differences, close to 20% of genes found to be differentially expressed in CRS were also found to be differentially expressed in the lower airways of asthmatics. Notable examples are IL6R, IL13RA2, MSMB, MUC5B, POSTN, SERPINB2, TFF2, WIF1 and WNT5A. Pathway analysis revealed that key processes represented by these shared genes are developmental pathway signaling, epithelial-mesenchymal transition and innate immune response, suggesting co-existence of epithelial remodeling and persistence of innate immune signals. Interestingly, many of the genes altered in CRS that we identified in the upper airways are also asthma susceptible genes previously identified through GWAS studies (e.g., IL1RL1, ORMDL3), indicating a common role for these genes in the pathogenesis of respiratory allergic diseases.
Regulatory function of interferon regulatory factor 3 in obesity, inflammation and insulin resistance (HUM7P.287)
Authors: Tang Peng , Zhang Yongliang 
Published: January 2023

Abstract
Obesity is a major risk factor for diseases ranging from insulin resistance, type 2 diabetes mellitus to nonalcoholic fatty liver disease. Obesity is associated with a state of chronic, low-grade inflammation. In this study, we found the important regulatory role of interferon regulatory factor 3 (IRF3), a master regulator of type I interferon-dependent immune responses, in obesity. We found that the expression of IRF3 was increased in white adipose tissue (WAT) from mice fed with high fat diet compared with that from mice fed with normal chow. IRF3 knockout (KO) mice developed obesity spontaneously with increased adiposity compared with wild-type (WT) controls. Deficiency of IRF3 in mice resulted in impaired insulin sensitivity and lipid homeostasis. The development of obesity in IRF3 KO mice was associated with increased infiltration of macrophages which was more inflammatory in the WAT compared with macrophages in WT mice. IRF3 deficient macrophages exhibited increased M1 polarization than WT cells. Additionally, IRF3 KO mice developed hepatic steatosis with increased expression of lipogenesis genes in the liver. Our study therefore demonstrated that IRF3 played an important role in the regulation of insulin sensitivity, inflammation and lipid homeostasis, which may provide a new strategy for treatment of obesity, type 2 diabetes mellitus and hepatic steatosis.
Cyclin-dependent kinase 5 contributes to adipose tissue inflammation in obesity through suppression of Treg differentiation (HUM7P.288)
Authors: Pareek Tej , Lam Eric , Letterio John 
Published: January 2023

Abstract
Homeostatic imbalance of regulatory and conventional T cells is linked with obesity-induced inflammation and insulin resistance. A decline in the number of both circulating and locally residing T regulatory (Treg) cells in adipose tissues is hallmark of adiposity, inflammation, and glucose intolerance. Recently, the signal transducer and activator of transcription 3 (Stat3) has been implicated as a critical mediator in this process; however, the factors that initiate this inflammatory cascade remain largely unclear. We recently reported a previously unknown function for Cyclin-dependent kinase 5 (Cdk5) in T cells, a kinase renowned otherwise for its role in regulating the development and function of cells in the neuronal lineage. Here we report for the first time that the mice lacking Cdk5 in T cells (Cdk5TKO-mice) are lean compared to their wild type littermates as confirmed by their body mass index, histopathological analysis of adipose tissue as well as complete body MRI scans measuring adiposity index. Moreover we observed a significant increase in circulating CD4+ CD25+ Foxp3+ Treg cells along with a marked decrease in Ser-727 phosphorylation of Stat3. Finally, both pharmacologic and genetic deletion of Cdk5 abrogates the IL6-mediated suppression of TGF-β-induced Treg differentiation. These results further solidify the role of Cdk5 as an essential regulator of T cell function and implicate Cdk5 as a potential therapeutic target for prevention and treatment of obesity.
Silencing of IL-17 modulates inflammatory and antimicrobial defense responses mediated by Propionibacterium acnes (HUM7P.291)
Authors: Agak George , Yu Yang , Qin Min , Park Andrew , Krutzik Stephan , Garban Hermes , Kim Jenny 
Published: January 2023

Abstract
Inflammation resulting from immune responses targeting Propionibacterium acnes plays a significant role in acne pathogenesis. We demonstrate that IL-17-expressing cells are present in skin biopsies from acne patients, and that P. acnes is a potent inducer of Th17-related cytokines, including IL-17 (inflammatory) and IL-22 (antimicrobial defense and tissue repair). Here we investigated whether silencing of IL-17 and IL-22 modulates Th17-related inflammatory and antimicrobial responses mediated by P. acnes. P. acnes stimulated peripheral blood mononuclear cells (PBMCs) demonstrated elevated expression of antimicrobial peptides (AMPs); psoriasin, cathelicidins, defensins, and antimicrobial chemokines; CXCL-1/-9/-10/-11 and CCL15 expression. siRNA-mediated knockdown of IL-17 led to loss of capacity to express and secrete IL-17, IL-22 and AMPs upon P. acnes stimulation. However, knocking-down IL-22 alone led to decreased AMP expression, but had no effect on the expression of genes known to directly signal Th17 responses including IL-17A, RORα and RORc. Both IL-17 and IL-22 were required for antimicrobial chemokines CXCL1 and CXCL10 expression, but not CXCL9, CXCL11 and CCL15. Importantly, IL-22 may play a role in modulating the IL-17-driven chronic inflammatory responses initiated by P. acnes and that treatments targeting the IL-17 pathway may be effective tools for acne therapy.
Myocyte enhancer factor-2 plays critical roles in HTLV-1 infection and transformation of CD4+ T cells associated with adult T cell leukemia (ATL) by stabilizing complex between Tax and CREB (HUM8P.335)
Authors: Jain Pooja 
Published: January 2023

Abstract
The exact molecular mechanisms regarding HTLV-1 Tax-mediated viral gene expression and CD4+ T cell transformation have yet to be fully delineated. Herein, utilizing virus infected primary CD4+ T cells and the virus-producing cell line, MT-2, we describe the role of myocyte enhancer factor-2 (MEF-2) in Tax-mediated transactivation of the LTR. Inhibition of MEF-2 expression by shRNA and its activity by HDAC9 led to reduced viral replication and HTLV-mediated T cell transformation in correlation with a heightened expression of MEF-2 in ATL patients. Mechanistically, MEF-2 was shown to be recruited to the HTLV-1 LTR followed by an assessment of MEF-2 binding site(s). A novel promoter-binding assay confirmed that MEF-2 constitutes the transcriptional complex that assembles on the LTR. Furthermore, an increase in MEF-2 expression was observed upon infection in an extent similar to CREB (the known Tax-interacting transcription factor) and HATs - p300, CBP, and p/CAF. Confocal imaging confirmed MEF-2 co-localization with Tax and these proteins were also shown to interact by co-immunoprecipitation. A number of MEF-2-integrated signaling pathways were activated during HTLV-1 infection of primary CD4+ T cells, including PI3K/Akt, NF-κB, MAPK, JAK/STAT and TGF-β possibly regulating MEF-2 activity. Overall, these studies are the first to describe the involvement and regulation of a novel transcription factor during the course of a retroviral infection and associated disease syndrome.
IL-7/Lymphopenia enhanced Type-I IFN response by modulating STAT-1 levels: its impact in CD4 T cell homeostasis (HUM8P.338)
Authors: Le Saout Cecile , Hasley Rebecca , Imamichi Hiromi , Tcheung Lueng , Hu Zonghui , Luckey Megan , Park Jung-Hyun , Durum Scott , Smith Mindy , Rupert Adam , Sneller Michael , Lane H. Clifford , Catalfamo Marta 
Published: January 2023

Abstract
HIV infection is associated with chronic immune activation and alteration of T cell homeostasis (CD4 T cell depletion and CD8 T cell expansion). While the acute CD4 depletion observed in the initial phase of HIV infection is likely due to direct cytopatic effects of the virus, the mechanism/s underlying the steady decline of the CD4 T cell pool during the chronic phase of infection are unclear and are felt to be associated with “immune activation”. In the current study, we addressed the impact of the combination of two distinct forces: homeostatic (CD4 T cell depletion) and inflammatory (HIV-driven IFN-α) on T cell homeostasis. We present evidences that IL-7 and lymphopenia enhanced CD4 T cell responsiveness to IFN-α by modulating expression of the Signal Transducers and Activators of Transcription (STAT) 1, 2 and 3. In a murine model, CD4 T cell depletion and CD8 T cell expansion were observed in a lymphopenic host chronically treated with IFN-α. These findings suggest that a synergistic interaction between lymphopenia and IFN-α may play a role in the pathogenesis of HIV infection. The analysis of this pathway may contribute to the development of new strategies to reverse the dysregulation of the T cell pools seen in patients with HIV infection.
Mucosal immune responses predict clinical outcomes during influenza infection independently of age and viral load (HUM8P.346)
Authors: Thomas Paul , Gartland Andrew , Wong Sook-San , Jeevan Trushar , Wang David , Roddam Philippa , Caniza Miguela , DeVincenzo John , Hertz Tomer , Webby Richard , Oshansky Christine 
Published: January 2023

Abstract
Children are an at-risk population for developing complications following influenza infection, but immunological correlates of disease severity are not understood. We hypothesized that innate cellular immune responses at the site of infection would correlate with disease outcome. To test this hypothesis, we established an observational cohort study with longitudinal sampling of peripheral and mucosal sites in 84 naturally influenza-infected individuals, including infants. Cellular responses, viral loads, and cytokines were quantified from nasal lavages and blood, and correlated to clinical severity. We found that while viral loads in children and adults were similar, innate responses in the airways were stronger in children and varied considerably between plasma and site of infection. Adjusting for age and viral load, an innate immune profile characterized by increased nasal lavage MCP-3, IFNα2 and plasma IL-10 levels at enrollment predicted progression to severe disease. Increased plasma IL-10, MCP-3, and IL-6 levels predicted hospitalization. This inflammatory cytokine production correlated significantly with monocyte localization from the blood to the site of infection, with conventional monocytes positively correlating with inflammation. Increased frequencies of CD14lo monocytes were in the airways of participants with lower inflammatory cytokine levels. An innate profile was identified that correlated with disease progression independent of viral dynamics and age.
Age-related gut dysbiosis contributes to age-related colitis and colon cancer risk and appears B7-H1-dependent. (HUM8P.352)
Authors: Cardenas Kim , Dao Vinh , Hurez Vincent , Curiel Tyler 
Published: January 2023

Abstract
Gut microbial imbalance (dysbiosis) can contribute to intestinal inflammation. Inflammation-driven colon cancer is a leading cause of death in the aged. We hypothesize that intestinal dysbiosis occurs with age and contributes to colon cancer susceptibility. We found that aged mice (~20 mos) had increased basal colon inflammation. Young mice (~3 mos) treated with AOM/DSS, an established model of inflammation-driven colon cancer, got transient colitis followed by colon cancer as expected. By striking contrast, aged mice on AOM/DSS developed severe, fatal, acute colitis preventing carcinogenesis studies. We also found that the colon microbiome is age-dependent. Gut flora-ablating antibiotics (abx) in young mice on AOM/DSS did not alter acute colitis or cancer. Strikingly, old mice on abx were highly protected from AOM/DSS-induced colitis and colon cancer, consistent with age-related dysbiosis causing increased risk for colitis and inflammation driven-colon cancer. PD-1 regulates gut flora in young mice and B7-H1 is its ligand. Aged B7-H1-/- mice given AOM/DSS, but no abx, did not develop acute colitis or colon cancer, suggesting that B7-H1 mediates age-related gut dysbiosis, inflammation and colon cancer risk. Taken together, our data suggest that age-related, B7-H1-dependent gut dysbiosis increases colon inflammation and susceptibility to colon carcinogenesis. Ongoing co-housing (WT/B7-H1 and young/aged) and other studies are defining specific immune mechanisms.
The NAD glycohydrolase CD38 regulates macrophage effector function and defense against Listeria monocytogenes. (INC7P.409)
Authors: Botta Davide , Rivero-Nava Laura , Lund Frances 
Published: January 2023

Abstract
CD38, an ecto-enzyme with ADP-ribosyl cyclase activity, is expressed on myeloid cells and has been shown to be a regulator of innate immunity and inflammation. Our study aimed to determine whether CD38 plays a role in the immune response to the Gram-positive bacterial pathogen Listeria monocytogenes (Lm). Following an intravenous Lm infection, Cd38-/- mice exhibited increased mortality and morbidity compared to wild-type mice. Analysis of tissue homogenates showed greater bacterial burden in the spleen and liver of Cd38-/- mice 3-4 days post infection, suggesting that early Lm resistance is CD38-dependent. Bone marrow chimera experiments revealed that the increased susceptibility of Cd38-/- mice was due to defects on myeloid lineage cells. While recruitment of PMNs, CD11b+ cells and NK cells to the spleen was not affected in Lm-infected CD38-/- mice, the efflux of monocytes from the bone marrow to the blood and spleen was significantly reduced. Expression levels of IL-10, an inhibitor of macrophage effector function, were elevated in serum and spleens of Lm-infected Cd38-/- mice, and splenocytes isolated from Lm-infected Cd38-/- mice had decreased nitric oxide production and TNFα secretion. Furthermore, in vitro stimulation experiments showed decreased expression of key inflammatory cytokines in activated CD38-deficient macrophages. Our data suggest that CD38 deficiency impairs macrophage effector function that is crucial for an effective early immune response to Lm.
Hematopoietic stem and progenitor cells expand into functional PMN at sites of S. aureus-infected wounds (INC7P.426)
Authors: Falahee Patrick , Granick Jennifer , Dahmubed Delsheen , Simon Scott 
Published: January 2023

Abstract
Staphylococcus aureus is a frequent cause of chronic nosocomial skin and soft tissue infections that can spread to muscle, bone and connective tissue. In response to infection, a heterogeneous population of circulating and bone marrow (BM)-derived cells are recruited to the site of injury where they collectively contribute to host defense and tissue repair. Polymorphonuclear leukocytes (PMN) serve a critical role as the first-line effectors responsible for innate immune protection against bacterial challenge. Using a transgenic mouse model of S. aureus-infected skin wounds, we recently reported that a subset of hematopoietic stem and progenitor cells (HSPC) that are lineage negative, Sca-1+ and c-kit+ (LSK cells) undergo local granulopoiesis and account for as much as 30% of total PMN within the abscess (Granick et al., 2013). Follow up studies show that LSK cells are stimulated directly by the agonist PAM3CSK4 in a manner dependent on TLR2/MyD88 and PGE2 signaling. We show that local granulopoiesis differs from myeloid proliferation within the BM revealing functional divergence of PMN produced at the site of wounding. Current efforts are focused on signaling effects of PGE2 that can manipulate the expansion capability of LSK during infection in wounds in order to gain an advantage over chronic and persistent Staphylococcus aureus infections.
Hepatic stellate cell-derived retinoic acid regulates group 3 innate lymphoid cells and modulates viral hepatitis (INC8P.432)
Authors: Jie Zuliang , Liang Yuejin , Hou Lifei , Soong Lynn , Cong Yingzi , Sun Jiaren 
Published: January 2023

Abstract
IL-17 and IL-22 are important for T cell priming and hepatoprotection in viral hepatitis, respectively; however, the source and regulation of these cytokines in the liver microenvironment are not well defined. Here, we present evidence for a significant expansion of intrahepatic cells producing IL-17 or IL-22 in mice during adenovirus infection. A subset of IL-17+ or IL-22+ cells expressed no myeloid/lymphoid lineage markers. Instead, they expressed high levels of stem-like markers, IL-7Rα (CD127) and RORγt, consistent with the newly described group 3 innate lymphoid cells (ILC3s). These cells contributed significantly to the establishment of the early cytokine milieu in virus-infected liver. Interestingly, retinoic acid increased in the liver following viral infection. Moreover, hepatic stellate cell (HSC)-derived retinoic acid promoted IL-22 production by ILC3s and protected liver from inflammatory response-related injuries. Notably, hepatic IL-7 was important for ILC3-derived IL-22 production. Blockade of IL-7Rα in vivo significantly decreased IL-22 levels and exacerbated hepatic inflammation. Collectively, this study has demonstrated the importance of a unique intrahepatic subpopulation ILC3 and its cytokine production during the initial stages of viral infection in the liver. Moreover, the cross talk among the hepatic stellate cell and innate immune cells plays a critical role in modulating immune responses in viral hepatitis.