bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin-22 controls RSV production in primary human airway epithelial cells by preserving cellular autophagy
Authors: Das Sudipta , Hu Sanmei , Chen Jie , St. Croix Claudette M , Kolls Jay K. , Ray Anuradha , Ray Prabir 
Published: January 2023

Abstract

OBJECTIVE
To study the ability of the host protective cytokine interleukin-22 (IL-22) to block productive infection of airway epithelial cells by Respiratory Syncytial Virus (RSV).

BACKGROUND
RSV infection can cause severe bronchiolitis and pneumonia in infants. However, no vaccine against RSV is currently available. RSV primarily infects both proximal and distal airways as well as alveolar epithelial cells in the lungs. IL-22 has mucosal-protective effects, known to preserve epithelial-barrier functions and promote host defense against pathogens. We, therefore, initiated studies to determine whether IL-22 can control RSV infection of airway epithelial cells (AECs).

METHODS
Primary human AECs differentiated under air-liquid interface (ALI) culture conditions were used for RSV infection (multiplicity of infection (MOI) 2) and then treated with IL-22 (50 ng/ml). 5-day old newborn C57BL/6 mice were intranasally infected with 1×106 PFU of RSV and then treated with an IL-22-Fc fusion protein (5 μg/mouse) intraperitoneally on day 3 p.i. Confocal imaging approach was utilized to determine co-localization of RSV and LC3B and to differentiate between autophagosomes and autolysosomes.

RESULTS
Treatment with IL-22 led to a significant decrease in viral load in primary human AECs as well as in vivo in mouse lungs. Confocal imaging and other approaches revealed subversion of the autophagic machinery by RSV for its own production, which was significantly inhibited by IL-22, thereby preserving autophagy in a STAT3 dependent manner.

CONCLUSIONS
IL-22 inhibits RSV production in both primary human airway epithelial cells and mouse lungs by preserving cellular autophagy thereby blocking hijacking of the autophagic apparatus by RSV.
Cytomegalovirus Blocks Macrophage TLR-mediated Tolerance through the Down-regulation of microRNA-146a to Enhance and Prolong Inducible Inflammatory Responses
Authors: Moran Monica Michelle , Dennis Evida A. , Smythies Lesley E. , Cong Yingzi , Sanchez Veronica , Britt William J. , Smith Phillip D. 
Published: January 2023

Abstract
Cytomegalovirus (CMV), a β-herpesvirus that persistently infects circulating monocytes, causes severe mucosal inflammation in the setting of immunosuppression. My laboratory has shown that CMV infection of monocytes upregulates toll-like receptor (TLR) expression and key components of the NF-κB signal transduction pathway, resulting in enhanced TLR-inducible inflammatory cytokine gene transcription and prompt, albeit transient, inflammatory cytokine production. However, the role of CMV in prolonged inflammation is not known. Here I investigated whether CMV prolongs macrophage-mediated inflammation by inhibiting tolerance to TLR stimulation, the process in which macrophages undergo profound down-regulation of inflammatory cytokine production after 24 hours. In addition to NF-κB induction of inflammatory cytokine production, NF-κB signaling induces microRNA146a (miR-146a), a regulatory miRNA that is induced 12 hours after the induction of inflammatory cytokine genes. Once transcribed, miR-146a feeds back to block IRAK1 and TRAF6, resulting in the downregulation of NF-κB-mediated gene transcription after 24 hours, thereby causing macrophages to become tolerant to subsequent TLR stimulation. Here we show that CMV potently suppresses miR-146a expression, preventing miR-146a blockade of the signal proteins IRAK1 and TRAF6 to promote NF-κB signal transduction. Thus, CMV suppression of macrophage miR-146a provides a mechanism by which CMV breaks macrophage tolerance to TLR stimulation, thereby promoting prolonged cytokine release. In conclusion, CMV enhances early TLR4- and TLR5-inducible cytokine production and blocks TLR tolerance, leading to prolonged cytokine-mediated inflammation.
The role of the bZIP transcription factor ZIP-1 in the Intracellular Pathogen Response of C. elegans
Authors: Lazetic Vladimir , Wu Fengting , Cohen Lianne B , Reddy Kirthi C , Troemel Emily R 
Published: January 2023

Abstract
How does the nematode Caenorhabditis elegans respond to natural pathogen infections with non-professional immune cells? To answer this question, we are studying the Intracellular Pathogen Response (IPR) – a host transcriptional response common to infection with molecularly diverse natural pathogens: microsporidia and the Orsay virus. In addition to intracellular pathogens, the IPR can be induced upon exposure to heat stress and proteasome inhibition. Mutant animals with constitutive IPR activation have increased intracellular pathogen resistance and thermotolerance, indicating that the IPR confers a protective response.
The IPR involves transcriptional activation of 80 genes, some of which are predicted to encode ubiquitin ligase components. One of the most highly induced IPR genes is pals-5, which serves as a robust readout for the IPR activation. Using pals-5::GFP reporters, we identified the predicted bZIP transcription factor ZIP-1 as a positive regulator of the IPR in two reverse genetic screens. Our qRT-PCR and smFISH studies demonstrated that ZIP-1 controls pals-5 mRNA expression early after proteasome blockade, but not at later time points. We further performed an RNA-Seq analysis, which revealed that ZIP-1 is required for mRNA expression of multiple IPR components. Based on the type of transcriptional regulation, we have identified three distinct types of IPR genes: a) completely ZIP-1-dependent, b) partially ZIP-1-dependent and c) ZIP-1-independent. Importantly, we found that ZIP-1 is required for the increased resistance to microsporidia infection in mutants with constitutive IPR expression, suggesting that ZIP-1-dependent genes play an important role in innate immunity.
Rhinovirus-infected COPD airway cells modulates innate immune function of alveolar macrophages via TGF-β1
Authors: Sajjan Uma 
Published: January 2023

Abstract
Airway epithelium, a primary target for rhinovirus (RV), modulates innate immune responses of other cell types including, pulmonary macrophages. The majority of RV-infected patients with chronic obstructive pulmonary disease (COPD) also acquire secondary bacterial infections. We hypothesized that COPD airway epithelial cells (AEC) affect pulmonary macrophage innate immune functions through secreted products, thus promoting secondary bacterial infections.
Pulmonary macrophages were pretreated with spent medium of RV- or sham-infected normal and COPD AEC and examined for innate immune responses to non-typeable H. influenzae (NTHI). Macrophages pretreated with spent medium from RV-infected COPD, but not normal AEC showed a defect in bacterial phagocytosis, and in the expression of cathelicidin, an antimicrobial peptide, and enhanced expression of CCL-20, TNF-α and CXCL-10 in response to NTHi. Proteomic analysis identified the presence of TGF-β1, tenascin C, fibronectin-1 in the secretome of RV-infected COPD, but not normal AEC. Neutralization of TGF-β1 abolished the inhibitory effects of spent medium from RV-infected COPD AEC on NTHi-induced cathelicidin and restored phagocytosis without significantly affecting NTHi-stimulated CCL-20, TNF-α and CXCL-10 in macrophages. These results indicate that RV-induced TGF-β1 secretion in COPD AEC attenuates the innate immune responses required for optimal clearing of bacteria by pulmonary macrophages and, this may increase the risk for acquiring secondary bacterial infections. At the same time, secretome from RV-infected COPD AEC may also increase inflammation via enhancing the bacteria-induced pro-inflammatory cytokines.
Fine tuning CD8+ T cell functional avidity by the PD-1/SHP2 axis
Authors: Li Jianping , Sui Yongjun , Berzofsky Jay A 
Published: January 2023

Abstract
T cells of high functional avidity recognize low antigen levels and have the most effective cytotoxic responses against viruses and tumor cells. Understanding the molecular regulations of T cell functional avidity is essential to aid novel vaccine design as well as adoptive immunotherapy by improving the T cell quality. Programmed cell death protein 1 (PD-1) is known to negatively regulate the signal strength of T cell receptor (TCR). Activated PD-1 recruits Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (Shp2), which dephosphorylates kinases involved in TCR signaling. However, it is unclear whether PD-1/SHP2 can modulate T cell functional avidity. To address this question, we treated splenocytes from OT-1 transgenic mice with anti-PD-1 or SHP099 (SHP2 inhibitor), or a combination of both for 3 days in a selective culture condition of APC-pulsed stimulation with 10−6 M or 10−9 M SINNFEKL, respectively. Our preliminary data showed that blocking SHP2/PD-1 enhanced functional avidity and antigen sensitivity of CD8+ T cell in vitro when stimulated with limited SINNFEKL antigen. Blocking of PD1/SHP2 also enhanced CD8 beta expression, which has been shown correlated with high functional avidity CD8+ T cells. These data suggest that PD1/SHP2 is involved in regulating T cell functional avidity.
A subset of mature neutrophils contains the strongest PMN-MDSC activity in blood and tissue of patients with head and neck cancer
Authors: Brandau Sven , Si Yu , Bruderek Kirsten , Merz Simon F , Jansen Philipp , Lang Stephan , Gunzer Matthias , Klode Joachim , Squire Anthony 
Published: January 2023

Abstract
A high neutrophil-to-lymphocyte ratio in the circulation and high frequencies of tumor-associated neutrophils (TAN) in malignant tissue are associated with poor outcome and tumor progression in patients with cancer. It is hypothesized that immunosuppressive neutrophil activity (aka PMN-MDSC activity) contributes to this effect. However, the exact cellular identity of human PMN-MDSC is still under debate. In this study, we sought to identify the neutrophil subset that contained the highest T cell suppressive activity. To this end, we purified different subsets of circulating neutrophils by FACS and performed multi-parameter immunofluorescence together with digital pathology on 2-D and 3-D tumor tissue samples.
We found that a population of circulating, mature, arginase I+ neutrophils that co-purified with mononuclear cells in density gradients, most potently suppressed T cell function in multiple in vitro assays. These PMN-MDSC were also superior to monocytic MDSC in T cell suppression. Using a novel technology of tissue whole mount labelling, clearing and imaging we derived 3-D spatial maps of neutrophil – T cell interaction in human tumors. We found that T cells, which were conjugated to arginase I+, myeloperoxidase+ TAN, had significantly reduced expression of proliferation and cytotoxicity markers. In patients, frequent conjugation of T cells to those PMN-MDSC was associated with poor prognosis. In contrast to circulating PMN-MDSC, tissue PMN-MDSC expressed high amounts of LOX-1 (oxidized low density lipoprotein receptor 1) and a high intratumoral frequency of LOX-1+ PMN-MDSC was associated with poor survival.
We identified and characterized PMN-MDSC activity in human cancer patients.
Glycolysis gene Hif1a negatively regulates the induction of intraepithelial CD4+CD8aa+ T cells
Authors: Sujino Tomohisa , Harada Yosuke , Nomura Ena , Miyamoto Kentaro , Tanemoto Shun , Yoshimatsu Yusuke , Kubota Yoshiaki , Kanai Takanori 
Published: January 2023

Abstract
Intestinal CD4 T cells reside in both lamina propria and intraepithelial lesion. We previously reported CD4+CD8aa+ intraepithelial lymphocytes (DPIELs) exhibit anti-inflammatory function against intestinal inflammation. Recently, metabolic status is important both for induction and for keeping cells in active phase. For example, Tregs use oxphos for cellular metabolism, while Th17 cells mainly use glycolysis. It is still unknown the metabolic status in tissue resident T cells and the effect of metabolic related gene for cell development in gut. By using mito-tracker and seahorse system, we first evaluated the metabolic status of tissue resident CD4 T cells. Then we used mouse model by deletion of the glycolysis related gene to uncover the development of intestinal resident CD4 T cells. The ratio of mitochondrial membrane potentialhipopulation of CD4IELs was increased in Germ free mice than in SPF mice. Most of DPIELs express the mitochondira membrane potentiallo. Although total CD4 positive IELs increased glycolysis compared to the splenic naive CD4 T cells, DPIELs expressed less pS6 and reduced glycolysis related gene, Hif1a. Next, We generated conditional Hif1a and Vhl ko mice (CD4cre: Hif1af/f: Hif1a (ΔCD4), CD4cre: Vhlf/f: Vhl (ΔCD4), CD4cre: Hif1af/f: Vhlf/f (DKO)) respectively to understand whether Hif1 was negatively regulated the induction of DPIELs or not. The ratio of DPIELs was increased in Hif1a (ΔCD4), DKO mice and decreased in Vhl (ΔCD4) mice. These results reveal total CD4IELs uses preferentially glycolysis, but glycolytic related gene Hif1a is negatively regulated the induction of DPIELs.
Discordant requirements for CD11c+ APCs in priming CD8 T cell responses against H-2Kb versus H-2Db restricted TMEV-associated peptides
Authors: Tritz Zachariah Peter , Orozco Robin , Malo Courtney , Ayasoufi Kathy , Yokanovich Lila , Goddery Emma , Khadka Roman , Fain Cori , Hansen Michael , Jin Fang , Johnson Aaron J 
Published: January 2023

Abstract
CD8 T cell priming after viral infection of the central nervous system (CNS) is incompletely understood. In peripheral infections, T cell priming generally relies upon stimulation by antigen-bearing dendritic cells (DCs) migrating into draining lymph nodes. The parenchyma of the brain, however, is largely devoid of dendritic cells and evidence demonstrating that activated DCs leave the brain parenchyma is lacking. We therefore sought to understand the role of DCs and specific MHC class I molecules in priming CD8 T cells following CNS infection. We employed H-2Db−/− H-2Kb−/− (MHC-I deficient) mice that express a floxed H-2Db or floxed Kb molecule, a unique transgenic mouse system developed by our research program. Crossed with an MHC class I deficient CD11c-Cre expressing animal results in DC-specific ablation of Db or Kb Class I restricted antigen presentation ability. We found that CD11c+ APCs are critical for the early priming of CD8 T cells against the Db restricted VP2121–130 epitope of the model pathogen, TMEV. However, DCs are ultimately dispensable for long-term development of these antigen specific T cells. Discordantly, the loss of MHC class I restricted antigen presentation ability on CD11c+ APCs does not impact the priming of T cells against the H-2Kb restricted OVA257–264 epitope following intracranial TMEV-OVA infection, but does impact the ability of these T cells to successfully occupy the CNS. This work suggests that differing patterns of MHC class I restriction for CNS pathogen-derived epitopes might have functional consequences on the APC requirements for a successful CD8 T cell response against neurotropic viruses.
Comparative evaluation of metabolic, electrophilic, and immunologic effects of itaconate and its ester derivatives on macrophage activation
Authors: Swain Amanda C , Bambouskova Monika , Kim Hyeryun , Duncan Dustin , Auclair Karine , Chubukov Victor , Simons Donald M. , Roddy Thomas P. , Stewart Kelly M. , Artyomov Maxim N. 
Published: January 2023

Abstract
Following the discovery of itaconate’s immunoregulatory properties, several ester derivatives of this dicarboxylic acid were designed to further examine its role. Here, we compare the metabolic, electrophilic, and immunologic profiles of macrophages treated with unmodified itaconate and a panel of itaconate derivatives. Using WT and Irg1-deficient macrophages, we show that neither dimethyl itaconate (DI) nor 4-octyl itaconate (4OI) are converted into intracellular itaconate in either resting or TLR-activated cells, 4-monoethyl itaconate (4EI) yields only small quantities of intracellular itaconate, while exogenous itaconic acid readily enters macrophages and accumulates to physiologically relevant amounts. We find that both DI and 4OI induce a strong electrophilic stress response, in contrast to itaconate and 4EI. This correlated with their differential immunological impact: DI and 4OI both inhibited IκBζ induction and IL-6 secretion. In contrast, itaconate treatment had minimal impact on IκBζ, IL-6 and pro-IL-1β levels, but demonstrated a distinct defect in IL-1β secretion. Altogether, this systematic evaluation stresses the importance of using unmodified itaconate in future mechanistic studies.
MEK1/2 blockade results in altered inflammatory response and delayed alveolar bone repair
Authors: Fonseca Angélica Cristina , Melchiades Jéssica Lima , de Campos Soriani Azevedo Michelle , Colavite Priscila Maria , Mortari Carolina Fávaro Francisconi , Tampanez André Petenuci , Garlet Gustavo Pompermaier 
Published: January 2023

Abstract
M1 and M2 macrophages play an important modulating role in tissue repair. In alveolar bone repair, the determinant these different phenotypes acquisition and its impact in repair process remains undefined, with a current assumption that assuming M2 conversion contributes to repair resolution. Considering MEK1/2 signaling pathway as a determinant for M2 polarization, the objective of this project was to evaluate the effect of MEK1/2 pharmacological inhibition in the local host response and repair outcome. C57Bl/6 (WT) mice, treated with MEK1/2i inhibitor PD0325901 (10mg/kg/24h/IP), which underwent extraction of the right upper incisor and, subsequently analyzed by computed microtomography (uCt) and histomorphometric analysis. uCt analysis, performed at 0,3,7 and 14 days periods revealed an overall smaller bone volume in MEK1/2i group, with a statistical difference in 14 days (p&lt;0,05 MEK1/2i versus Control). These results, when combined with the histomorphometric analysis, reveals a delay in the alveolar bone repair process in the MEK1/2i group, characterized at 7 days by a higher density of connective tissue parameters, specifically collagen fibers, blood vessels, inflammatory cells and blood clot, when compared with control group. Additionally, a lower density of bone tissue parameters, specifically osteoblasts, osteoclasts and bone matrix, where observed upon MEK1/2i inhibition. Therefore, partially, the results show that MEK1/2 inhibitory effect results in delayed alveolar bone repair, initially involving the control of inflammatory cell migration and subsequent bone formation.
Supported by grants from FAPESP (2018/10177-9 and 2015/24637-3)
Immunologic outcomes of bidirectional cross talk between gamma delta T cells and dendritic cells is context dependent
Authors: Biradar Shivkumar , Lotze Michael , Mailliard Robbie B 
Published: January 2023

Abstract
T cells expressing the gamma delta (γδ) T cell receptor are a minor cell population, but a critical component of innate immunity. γδ T cells can also influence adaptive immunity through their functional impact on dendritic cells (DC). To investigate the interaction between these cell types, we co-cultured peripheral blood γδ T cells from healthy volunteers with autologous monocyte derived DC. When immature DC (iDC) were co-cultured with resting human γδ T cells in the presence of zoledronate (Zol), drug that activates Vγ9δ2 T cells, DC maturation occurred. Blocking studies determined that γδ T cell-induced DC maturation was partially mediated by TNF-a and IFN-g. Moreover, γδ T cell-activated DC produced enhanced levels of IL-12p70. Interestingly, when activated effector γδ T cells were co-cultured with iDC in the presence of Zol a high degree iDC cell death was noted, suggesting a regulatory role of γδ T cells. When studying the impact of mature DC on γδ T cell function, we found that IL-12p70 deficient PGE-2 matured DC had a higher capacity to expand resting γδ T cells, that expressed higher levels of CD16, and were particularly less sensitive to apoptosis than those co-cultured with high IL-12p70-producing interferon-matured DC. Our findings show that the outcome of bidirectional cross talk between γδ T cells and DC is dependent on the context and activation status of each cell type, and that each regulate and modulate the immune function of the other.
The interaction between group 2 innate lymphoid cells and lipid metabolism
Authors: Zhang Yingyu , Huang Yuefeng 
Published: January 2023

Abstract
Innate lymphoid cells (ILCs) have been found in many tissue sites but are enriched in barrier surfaces such as intestine, lung and skin. They lack antigen-specific receptors yet respond to alarmin signals that are released by tissue, to resemble the cytokine production and effector function of T cells. ILCs play important roles in host defense, tissue repair, autoimmune disorders, inflammation, metabolic homeostasis and more. Recent progress in immunometabolism has highlighted the diverse roles of lipid metabolism in the response and function of immune cells including lymphocytes. But the interaction between ILC2s and lipid metabolism is poorly understood. Our preliminary studies show that, upon activation, intestinal ILC2s significantly upregulate the expression of several genes that are important for cholesterol metabolism. Cholesterol is an essential structural component of mammalian cell membranes and is the precursor for bile acids, vitamin D and steroid hormones. Cholesterol metabolism disorder leads to severe diseases such as hypercholesterolemia, atherosclerosis and diabetes. By using various mouse models and multi-disciplinary experimental approaches, we will study if and how cholesterol regulates the homeostasis, activation and cytokine production of ILC2s and if cholesterol regulation on ILC2s contributes to host defense against helminth infection. We will also investigate if ILC2s in turn modulate lipid, especially cholesterol, metabolism and if ILC2s play any role in hypercholesterolemia or atherosclerosis.
Differential Response of Dendritic Cells and Macrophages to Signals from Airway Epithelial Cells in Humans
Authors: Agrawal Anshu , Agrawal Sudhanshu , Monteiro Clarice , Mohammadi Reza 
Published: January 2023

Abstract
Airway epithelial cells (AECs), dendritic cells (DCs) and alveolar macrophages are the primary cells involved in respiratory immunity and tolerance. Since DCs and macrophages exist in close proximity to AECs, the function of both these cells is influenced by AECs. Using a 2D model to study the interaction of human primary bronchial epithelial cells (representative of AECs) with DCs we have recently demonstrated that AECs enhance the immune surveillance capacity of myeloid DCs (mDCs) from the circulation at homeostasis. Culture of mDCs with AECs resulted in the upregulation of pathogen recognition receptors (PRRs) and downstream signaling molecules which were reflected in the enhanced inflammatory cytokine responses to Klebsiella pneumoniae LPS. In contrast to circulatory mDCs, culture of macrophages with AECs led to a significant inhibition of LPS induced proinflammatory responses. More importantly, AECs induced the secretion of TGF-β and IL-10 from macrophages even in the absence of LPS stimulation. Furthermore, macrophages exposed to AECs induced significantly increased level of T regulatory cells. Thus, it seems AECs induce tolerance in macrophages but enhance the immunogenicity of mDCs suggesting a division of labor between DCs and macrophages in the respiratory mucosa. Investigation into the possible mechanisms for this differential response indicates that exosomes from AECs may be partially responsible for inducing tolerance in macrophages while growth factors secreted by AECs may be involved in priming DCs. These data demonstrate that AECs secrete different mediators that enhance immunogenicity and tolerance in the respiratory tract. These mediators may potentially be used to modulate respiratory immunity.