bluuebunny/crossref_metadata_2025_split huggingface dataset:
Binge ethanol exposure alters alveolar macrophage activation in burn-injured mice (INC5P.329)
Authors: Ippolito Jill , Curtis Brenda , Ramirez Luis , Kovacs Elizabeth 
Published: January 2023

Abstract
Alcohol intoxication is involved in 50% of all burn injuries, resulting in an increased risk of lung infection and failure, relative to burn alone. Our work has shown that in a mouse model of episodic binge ethanol exposure followed by burn injury there is prolonged pulmonary inflammation, relative to burn alone. The magnitude of pulmonary inflammation is mediated in part by alveolar macrophages (AMs), thus we examined the effect of ethanol on AM activation. Thirty minutes after binge ethanol exposure, mice were anesthetized and given a 15% total body surface area dorsal scald injury. At 24 and 72 hrs post-injury bronchoalveolar lavage AM granularity was assessed by flow cytometry using side scatter (SSC). At 24 hrs, 12% of AMs from burn alone had high SSC relative to 1.5% of AMs from sham groups (p&lt;0.05). Only 6% of AMs from combined injured had high SSC. By 72 hrs, 3% of AMs from both burn groups had high SSC. Anti-inflammatory M2 phenotype of high SSC AMs was assessed using M2 marker CD206. At 24 hrs, there was no change in CD206. At 72 hrs, AMs from burn alone had a 43% increase in CD206 relative to sham groups. Giving ethanol prior to burn further elevated the expression of this marker by 46% over burn alone. These data indicate ethanol exposure prior to burn injury can differentially alter AM phenotype at early and later time points.
Memory T cell-derived IFN-gamma instructs potent innate cell activation for protective immunity (INC6P.349)
Authors: Lauvau Gregoire , M'Homa Soudja Saidi , Chandrabos Ceena , Yakob Ernest , Veenstra Mike , Palliser Deborah 
Published: January 2023

Abstract
Cells of the innate immune system are essential for host defenses against primary microbial pathogen infections, yet their involvement in effective memory responses of vaccinated individuals has been poorly investigated. Here we show that memory T cells instruct innate cells to become potent effector cells in a systemic and a mucosal model of infection. Specifically, we found that memory T cells control phagocyte, dendritic cell and NK/NK T cell mobilization and induction of a strong program of differentiation which include their expression of effector cytokines and microbicidal pathways, all of which are delayed in non-vaccinated hosts. Disruption of IFN-gamma-signaling inside Ly6C+ monocytes, dendritic cells and macrophages impairs these processes and the control of pathogen growth. These results reveal how memory T cells, through rapid secretion of IFN-gamma, orchestrate extensive modifications of host innate immune responses that are essential for effective protection of vaccinated hosts.
The immunomodulatory drug lenalidomide augments NK cell IFN-γ secretion and lowers the threshold for NK cell activation (INC6P.351)
Authors: Lagrue Kathryn , Chopra Rajesh , Davis Daniel 
Published: January 2023

Abstract
The immunomodulatory drug lenalidomide is widely used for the treatment of multiple myeloma. NK cells can kill tumour cells in early stage myeloma but there is a decline in NK cell cytotoxicity as the disease progresses. Previous studies have shown that lenalidomide increases antibody-dependent cellular cytotoxicity, yet little is known about its effects on cytokine secretion. Here, we show that lenalidomide increases IFN-γ secretion from primary human NK cells stimulated by NK-sensitive target cells. Moreover, after ligation of NK activating receptors CD16 and NKG2D, lenalidomide caused a 2-fold increase in the proportion of primary NK cells producing IFN-γ, and a 10-fold increase in the amount of IFN-γ produced per cell. This implies that lenalidomide acts downstream from early membrane-proximal signalling, which is distinct for these two receptors. In addition, lenalidomide-treated NK cells displayed a 2-fold decrease in the amount of ligand required to reach 50% of maximal activation, establishing that lenalidomide lowers the threshold for NK cell activation. Finally, using super resolution microscopy, we found that lenalidomide treatment increases the periodicity of the actin meshwork at the immune synapse during cytokine secretion, a cytoskeletal rearrangement likely to be important for its mechanism of action. Taken together, these results establish that lenalidomide influences cytokine secretion and lowers the threshold for NK cell activation.
Therapeutic effects of a natural compound isolated from garlic (Allium sativum L.), against experimental polymicrobial sepsis (INC6P.335)
Authors: Ok Chang Youp , Lee Sung Kyun , Park Yoo Jeong , Jung Young Su , Lee Ha Young , Kim Sang Doo , Jung Won Jung , Kim Do Yeon , Choi Young Whan , Bae Yoe-Sik 
Published: January 2023

Abstract
Sepsis is a serious infectious life threatening disease. In this study, we demonstrate that LII-34, a natural compound isolated from garlic (Allium sativum L.), markedly enhances survival rate, by inhibiting lung inflammation in cecal ligation and puncture (CLP) experimental polymicrobial sepsis model. LII-34 strongly reduced bacterial colony unit from peritoneal fluid in CLP mice by stimulating generation of reactive oxygen species. Lymphocyte apoptosis from spleen in CLP mice was also markedly decreased by LII-34 administration. LII-34 also significantly inhibits the production of proinflammatory cytokines such as TNF-α, interleukin-1β (IL-1β) and IL-6 in CLP mice. Lipopolysaccharide-stimulated the production of TNF-α, CCL2, IL-6, and IL-10 are also strongly inhibited by LII-34 in mouse bone marrow-derived macrophages. Taken together, our results indicate that LII-34 shows therapeutic effect against polymicrobial sepsis by enhancing microbial killing and blocking cytokine storm. Chang Youp Ok and Sung Kyun Lee are equally contributed to this work.
The kidney myeloid cell compartment is perturbed in diabetic BTBR ob/ob mice (INC6P.338)
Authors: Fink Lisbeth , Gotfredsen Carsten , Rosendahl Alexander , Pedersen Maiken 
Published: January 2023

Abstract
The BTBR ob/ob mouse is gaining interest as a model of diabetic nephropathy, because it develops progressive albuminuria and, as opposed to the db/db diabetic mouse, is considered to develop fibrotic kidney lesions. The mouse kidney contains multiple types of resident mononuclear phagocytes and neutrophils. In the Akita type 1 diabetes mouse model, macrophage recruitment has been shown to be a key driver of the diabetic nephropathy, and human diabetic nephropathy kidney specimens display increased macrophage infiltration. We aimed to study the myeloid cell populations locally in the BTBR ob/ob kidney. The major myeloid cell population, the macrophage-like cells (CD68+F4/80+), was increased in diabetic, proteinuric BTBR ob/ob mice compared to normo-glycemic BTBR ob/+ mice, whereas monocyte-like cells (CD68+F4/80-) were decreased. In addition, kidney neutrophil counts were reduced in the diabetic mice. Consistent with the overall increase in myeloid cell numbers caused by the increase in macrophages, ICAM-1 expression on endothelial cells was significantly increased. In conclusion, proteinuria in the BTBR ob/ob mouse model of diabetic nephropathy is accompanied by a modulated inflammatory state in the kidney myeloid cell compartment, potentially contributing to the glomerulosclerosis and interstitial fibrosis observed in this model.
Transient receptor potential melastatin 2 protects mice against polymicrobial sepsis by enhancing bacterial clearance (INC6P.342)
Authors: Fang XiangMing 
Published: January 2023

Abstract
Background: Recent studies suggest that transient receptor potential melastatin 2 (TRPM2) channel plays an important role in inflammation and immune response. However, the role and mechanism of TRPM2 in polymicrobial sepsis remains unclear. Methods: We explored the effects of genetic disruption of TRPM2 on mortality, bacterial clearance, organ injury, and systemic inflammation during cecal ligation and puncture (CLP)-induced sepsis. Electrophysiology, immunoblot, bacterial clearance experiment, and quantitative real-time polymerase chain reaction were used to explore the role and mechanism of TRPM2 in sepsis. Results: After CLP, Trpm2-KO mice had increased mortality compared with WT mice. The increased mortality was associated with increased bacterial burden, organ injury, and systemic inflammation. Disruption of TRPM2 decreased HO-1 expression and increased bacterial burden in bone marrow-derived macrophages (BMDMs). Pretreatment of Trpm2-KO mice with HO-1 inducer reversed the susceptibility of Trpm2-KO mice to sepsis by enhancing bacterial clearance. In addition, septic patients with lower monocytic TRPM2 and HO-1 mRNA levels had a worse outcome compared with septic patients with normal monocytic TRPM2 and HO-1 mRNA levels. TRPM2 levels correlated with HO-1 levels in septic patients. Conclusions: Our data demonstrate a protective role of TRPM2 in controlling bacterial clearance during polymicrobial sepsis, possibly by regulating HO-1 expression.
Caspase-1-independent interleukin-1β is required for clearance of bordetella pertussis infections and whole-cell vaccine-mediated immunity (INM6P.413)
Authors: Place David , Muse Sarah , Kirimanjeswara Girish , Harvill Eric 
Published: January 2023

Abstract
Whooping cough remains a significant disease worldwide and its re-emergence in highly vaccinated populations has been attributed to a combination of imperfect vaccines and evolution of the pathogen. The focus of this study was to examine the role of IL-1α/β and the inflammasome in generation of the interleukin-1 (IL-1) response, which is required for the clearance of B. pertussis. We show that IL-1β but not IL-1α is required for mediating the clearance of B. pertussis from the lungs of mice. We further found that IL-1β and IL-1R deficient mice have normal but persistent levels of inflammation, characterized by immune cell infiltration, with significantly increased IFNγ and a normal IL-17A response during B. pertussis infection. Contrary to expectations, the cleavage of precursor IL-1β to its mature form did not require caspase-1 during primary infections within the lung despite being required by bone marrow-derived macrophages exposed to live bacteria. We also found that the caspase-1 inflammasome was not required for protective immunity against a B. pertussis challenge following vaccination with heat-killed whole cell B. pertussis, despite IL-1R signaling being required. These findings demonstrate that caspase-1-independent host factors are involved in the processing of protective IL-1β responses that are critical for bacterial clearance and vaccine-mediated immunity.
Activation of AIM2 inflammasome triggers mitochondrial damage and blocks mitophagy (INM6P.409)
Authors: Yu Jiujiu , Murakami Tomohiko , Nagasu Hajime , Horng Tiffany 
Published: January 2023

Abstract
The AIM2 inflammasome is critical for host defense against certain intracellular bacteria and DNA viruses. It is a cytoplasmic complex consisting of the regulatory subunit AIM2, the adaptor ASC, and the effector subunit caspase-1. Stimulus dependent assembly of the complex activates the proteolytic activity of caspase-1, which is required for the processing and production of inflammatory cytokines IL-1β and IL-18. Here we demonstrate that mitochondrial damage is a consequence of activation of the AIM2 inflammasome. We address the underlying mechanisms, thus providing insight into regulation of a key inflammasome effector activity.
POP3 is a novel inhibitor of ALR inflammasomes and controls host defense to DNA virus infections (INM6P.411)
Authors: Stehlik Christian , Khare Sonal , Ratsimandresy Rojo , de Almeida Lúcia , Cuda Carla , Rellick Stephanie , Misharin Alexander , Wallin Melissa , Gangopadhyay Anu , Forte Eleonora , Gottwein Eva , Perlman Harris , Reed John , Greaves David , Dorfleutner Andrea 
Published: January 2023

Abstract
The innate immune system responds to infections and tissue damage by activating cytosolic sensory complexes called inflammasomes. Cytosolic DNA is sensed by AIM2-like receptors (ALRs) during bacterial and viral infections and in autoimmune diseases. Subsequently, recruitment of the adaptor protein ASC through PYRIN domain (PYD)-PYD interaction, links ALRs to the activation of caspase-1 and subsequent maturation of the proinflammatory cytokines IL-1β IL-18 and induction of pyroptotic cell death. A controlled inflammasome response is crucial for maintaining homeostasis, whereas excessive and uncontrolled cytokine production contributes to autoinflammatory diseases. However, ALR inflammasome regulation is poorly understood. Here, we identified the type I interferon (IFN)-inducible PYD-only protein 3 (POP3) as a binding partner of ALRs. POP3 competes with ASC for recruitment to ALRs and thereby inhibits DNA virus-induced ALR inflammasome activation and IL-18 and IFN-γ-dependent host defense in vivo. A mouse model with macrophage-specific POP3 expression recapitulates global AIM2 deficiency and thus, emphasizes the importance of ALR inflammasome regulation in the monocytic/macrophage lineage. Collectively, we show that POP3 represents one of the type I IFN response factors that regulate human and mouse ALR inflammasomes in macrophages within a type I IFN-regulatory loop.
Macrophage anti-viral responses to diabetogenic encephalomyocarditis viruses are mediated by oxidative stress (INM7P.426)
Authors: Burg Ashley , Tse Hubert 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic β-cells. Both human and rodent studies suggest that viral infections trigger this process. Proinflammatory cytokines and reactive oxygen species (ROS) produced during an anti-viral response are also considered drivers of T1D. We recently demonstrated that Non-Obese Diabetic (NOD) mice deficient in NADPH oxidase (NOX)-derived ROS (NOD.Ncf1m1J) were highly resistant to T1D, and bone marrow-derived macrophages (BMMΦ) from these mice had reduced anti-microbial responses to LPS and poly(I:C), a viral dsRNA mimic. Therefore, we hypothesize that loss of NOX-derived ROS will reduce the diabetogenicity of viral infections by dampening the innate immune anti-viral response. To this end, we infected BMMΦ with diabetogenic (EMCV-D) or non-diabetogenic (EMCV-B) Encephalomyocarditis viruses. NOD.Ncf1m1J BMMΦ showed significant decreases in TNFα upon EMCV-D (1.2-fold, p&lt;0.004) and EMCV-B (1.5-fold, p&lt;0.0001) infection compared to NOD. This was concomitant with lower protein expression of the viral sensor, RIG-I. Interestingly, only EMCV-D elicited an IL-1β response, which was dramatically reduced (1.9-fold, p&lt;0.0001) in NOD.Ncf1m1J BMMΦ. Our results highlight a crucial role for NOX-derived ROS in the innate response to EMCV infection. Future studies will define the impact of ROS on human anti-viral responses to diabetogenic viruses.
IL22 and CD160 play additive roles in the mucosal host response to Clostridium difficult infection in mice (INM8P.435)
Authors: Sadighi Akha Amir , McDermott Andrew , Carlson Paul , Frank Charles , McDonald Roderick , Falkowski Nicole , Bergin Ingrid , Huffnagle Gary 
Published: January 2023

Abstract
We have previously shown the significant up-regulation of Il22 and increased phosphorylation of STAT3 as part of the mucosal response to C. difficile VPI 10463 infection. Others have shown that phosphorylation of STAT3 at mucosal surfaces includes IL22- and CD160-mediated components. The current study sought to determine the potential role(s) of IL22 and/or CD160 in the mucosal response to C. difficile infection. Infection of mice with C. difficile 630 led to the significant induction of STAT3 phosphorylation and a very similar set of genes in the colon as we had reported previously. C. difficile-infected mice treated with anti-IL22, anti-CD160 or both showed significantly reduced STAT3 phosphorylation in comparison to C. difficile-infected mice that had received neither antibody. In addition, C. difficile-infected mice treated with anti-IL22/CD160 induced a smaller set of genes, and at significantly lower levels than the untreated C. difficile-infected mice. These included pro-inflammatory chemokines and cytokines and anti-bacterial peptides. In addition, mice treated with anti-IL22/CD160 had a lower influx of neutrophils than the other 3 infected groups. These data demonstrate that IL22 and CD160 are together responsible for a significant fraction of the colonic STAT3 phosphorylation in C. difficile infection. They also underscore the additive effects of IL22 and CD160 in mediating both the pro-inflammatory and pro-survival aspects of the mucosal response in this infection.
Participation of the transient receptor potential melastatin 2 ion channel in oxidative stress response and host defense during Helicobacter pylori infection (INM8P.448)
Authors: Algood Holly , Beceiro Susana , Chatuverdi Rupesh , Horvath Dennis , Cortado Hanna , Wilson Keith , Partida-Sanchez Santiago 
Published: January 2023

Abstract
Helicobacter pylori (Hp) is a dominant member of the gastric microbiota in a majority of the world’s population. Hp colonization has been attributed to detrimental outcomes including gastritis and gastric cancer. The immune response to Hp leads to elevated levels of reactive oxygen species and reactive nitrogen species within the gastric mucosa. The redox-sensitive cation channel TRPM2 is activated by direct binding of ADP ribose and under conditions of oxidative and metabolic stress by H2O2 and H+. TRPM2 is strongly expressed in immune cells of the phagocytic lineage, themselves professional oxidants-generators. Here we report that Hp infection of TRPM2-deficient macrophages resulted in higher rates of bacterial killing and increased levels of proinflammatory cytokines and NOX2 compared to wild-type macrophages. Consequently, TRPM2-deficient macrophages displayed significantly higher ROS production during Hp infection, suggesting an increased NADPH oxidase activity. In vivo, when TRPM2-deficient mice were infected orogastrically with Hp their gastric tissues exhibited an increased NOX2 expression and myeloperoxidase activity compared to wild-type mice. Furthermore, enhancement of NADPH oxidase activity in TRPM2-deficient animals increased inflammation and reduced bacterial burden when compared with wild-type mice. Taken together, these data indicate that TRPM2 establishes a negative feedback of ROS production through phagosomal NADPH oxidase during Hp infection.
ApoE3 blocks HCV entry inhibitor ficolin-2 (INM8P.437)
Authors: Zhang Xiao-Lian , Yushan Ren Yushan , Zhao Yinglan 
Published: January 2023

Abstract
Human ficolin-2 is a lectin-complement pathway activator that is present in normal human plasma and is associated with infectious diseases; however, little is known regarding the roles and mechanisms of ficolin-2 during chronic Hepatitis C Virus (HCV) infection. In this study, we found that ficolin-2 could inhibit the entry of HCV at the early stage of virus infection, regardless of the viral genotype. Ficolin-2 neutralized and inhibited the initial attachment and infection of HCV by binding to the HCV envelope surface glycoproteins E1 and E2, blocking HCV attachment to low-density lipoprotein receptor (LDLR) and scavenger receptor (SR-B1), and weakly interfering with CD81 receptor attachment. However, no interference with claudin-1 and occludin receptors attachment was observed. The C-terminal fibrinogen domain of ficolin-2 was identified as the critical binding region for the HCV E1-E2 N-glycans, playing a critical role in the anti-HCV activity. Our data suggest that the HCV entry inhibitor ficolin-2 is a novel and promising antiviral innate immune molecule and the immune escape mechanism mediated by ApoE3 during chronic HCV infection. HCV may be neutralized using compounds directed against the lipoprotein moiety of the viral particle and that ApoE3 may be a new target to combat HCV infection.
Endomembrane structures utilized by pathogens are targeted for disruption by the ubiquitin-like conjugation systems of autophagy (INM8P.439)
Authors: Hwang Seungmin , Choi Jayoung , Biering Scott , Park Sunmin , Virgin Herbert 
Published: January 2023

Abstract
Autophagy is an evolutionarily conserved pathway that sequesters cytoplasmic materials in double membrane bound autophagosomes and degrades the cargo through the fusion between the autophagosome and lysosome. Degradative autophagy has been shown to play crucial roles in immune defense against intracellular pathogens as well as its conventional roles in recycling and remodeling. We found that the ubiquitin-like conjugation systems of the autophagy pathway involved in the conjugation of microtubule associated protein 1 light chain 3 (LC3) to phosphatidylethanolamine on autophagosome membrane, including E1 Atg7, E2 Atg3, and E3 Atg12-Atg5-Atg16L1 complex, play crucial roles in the control of Murine Norovirus and Toxoplasma gondii both in vitro and in vivo. Pharmacologic modulation of the degradative autophagy pathway or genetic deletion of the other essential autophagy genes had no significant effects on controlling the replication of the pathogens by interferon-gamma (IFNγ). Rather the ubiquitin-like conjugation system was required for targeting of LC3 and IFNγ induced effectors onto the endomembrane structures utilized by the pathogens for their replication and consequent disruption of the structures. These data suggest that the ubiquitin-like conjugation systems that reorganize endomembranes during canonical autophagy have evolved to target immune effectors to the endomembrane structures utilized by pathogens as a form of cell autonomous immunity.
Host innate immune responses are different for high and low pathogenicity influenza A virus subtypes (INM8P.443)
Authors: Gupta Goutam , Pardington Paige , Chaudhary Anu , Zeytun Ahmet , Harris Jennifer , Ribeiro Ruy 
Published: January 2023

Abstract
Different influenza A virus subtypes display different pathogenicity during host infection. It is our hypothesis that the host innate immune defense inversely correlates with the viral pathogenicity, i.e., the higher the viral pathogenicity the lower is the host innate immune defense and vice versa. In order to test our hypothesis, we monitored infection of normal human bronchial epithelial cells due to high pathogenicity H1N1 and low pathogenicity H3N2 subtypes during the early stages (0 to 24 hours) of infection. Specifically, we performed whole genome microarray analysis of the infected cells, identified the genes significantly altered in their expression, and validated the expression patterns of these genes by real-time qPCR. Of particular importance were the inducer and effector genes in the IFN-α/β pathway, a prominent innate immune response against viral infection. The prominent inducers include: (i) the OAS genes involved in the production of small viral RNA, (ii) the viral RNA sensors RIG-I, MDA-5, and TLR3, and (iii) the IRF transcription factors involved in the expression of IFN-α/β. The prominent effectors include: (i) ISG15, which activates RIG-I by ubiquitination, (ii) RSAD2 which inhibit the budding of influenza A virus, and (iii) GBPs, which inhibit viral replication. We validate our hypothesis by demonstrating that the release and expression of inducers and effectors of IFN-α/β are lower in high pathogenicity H1N1 than those in low pathogenicity H3N2. .