Medicine and Health Sciences Commons^™

Chemotherapy Activates Inflammasomes To Cause Inflammation-Associated Bone Loss, Chun Wang, Khushpreet Kaur, Canxin Xu, Yousef Abu-Amer, Gabriel Mbalaviele

2020-Current year OA Pubs

Chemotherapy is a widely used treatment for a variety of solid and hematological malignancies. Despite its success in improving the survival rate of cancer patients, chemotherapy causes significant toxicity to multiple organs, including the skeleton, but the underlying mechanisms have yet to be elucidated. Using tumor-free mouse models, which are commonly used to assess direct off-target effects of anti-neoplastic therapies, we found that doxorubicin caused massive bone loss in wild-type mice, a phenotype associated with increased number of osteoclasts, leukopenia, elevated serum levels of danger-associated molecular patterns (DAMPs; e.g. cell-free DNA and ATP) and cytokines (e.g. IL-1β and IL-18). Accordingly, …

Dna Hypomethylation Ameliorates Erosive Inflammatory Arthritis By Modulating Interferon Regulatory Factor-8, Gaurav Swarnkar, Nicholas P Semenkovich, Manoj Arra, Dorothy K Mims, Syeda Kanwal Naqvi, Timothy Peterson, Gabriel Mbalaviele, Chia-Lung Wu, Yousef Abu-Amer

2020-Current year OA Pubs

Epigenetic regulation plays a crucial role in the pathogenesis of autoimmune diseases such as inflammatory arthritis. DNA hypomethylating agents, such as decitabine (DAC), have been shown to dampen inflammation and restore immune homeostasis. In the present study, we demonstrate that DAC elicits potent anti-inflammatory effects and attenuates disease symptoms in several animal models of arthritis. Transcriptomic and epigenomic profiling show that DAC-mediated hypomethylation regulates a wide range of cell types in arthritis, altering the differentiation trajectories of anti-inflammatory macrophage populations, regulatory T cells, and tissue-protective synovial fibroblasts (SFs). Mechanistically, DAC-mediated demethylation of intragenic 5'-Cytosine phosphate Guanine-3' (CpG) islands of the …

Prenatal Exposure To Maternal Disadvantage-Related Inflammatory Biomarkers: Associations With Neonatal White Matter Microstructure, Ashley F P Sanders, Brian Tirado, Nicole A Seider, Regina L Triplett, Rachel E Lean, Jeffrey J Neil, J Philip Miller, Rebecca Tillman, Tara A Smyser, Deanna M Barch, Joan L Luby, Cynthia E Rogers, Christopher D Smyser, Barbara B Warner, Et Al.

2020-Current year OA Pubs

Prenatal exposure to heightened maternal inflammation has been associated with adverse neurodevelopmental outcomes, including atypical brain maturation and psychiatric illness. In mothers experiencing socioeconomic disadvantage, immune activation can be a product of the chronic stress inherent to such environmental hardship. While growing preclinical and clinical evidence has shown links between altered neonatal brain development and increased inflammatory states in utero, the potential mechanism by which socioeconomic disadvantage differentially impacts neural-immune crosstalk remains unclear. In the current study, we investigated associations between socioeconomic disadvantage, gestational inflammation, and neonatal white matter microstructure in 320 mother-infant dyads over-sampled for poverty. We analyzed maternal …

Multiomic Profiling Reveals Metabolic Alterations Mediating Aberrant Platelet Activity And Inflammation In Myeloproliferative Neoplasms, Fan He, Angelo Ba Laranjeira, Tim Kong, Shuyang Lin, Katrina J. Ashworth, Alice Liu, Nina M. Lasky, Daniel Ac Fisher, Maggie J. Cox, Mary C. Fulbright, Lilian Antunes-Heck, Layow Yu, Molly Brakhane, Bei Gao, Stephen M. Sykes, Angelo D'Alessandro, Jorge Di Paola, Stephen T. Oh

2020-Current year OA Pubs

Platelets from patients with myeloproliferative neoplasms (MPNs) exhibit a hyperreactive phenotype. Here, we found elevated P-selectin exposure and platelet-leukocyte aggregates indicating activation of platelets from essential thrombocythemia (ET) patients. Single-cell RNA-seq analysis of primary samples revealed significant enrichment of transcripts related to platelet activation, mTOR, and oxidative phosphorylation in ET patient platelets. These observations were validated via proteomic profiling. Platelet metabolomics revealed distinct metabolic phenotypes consisting of elevated ATP generation accompanied by increases in the levels of multiple intermediates of the tricarboxylic acid cycle, but lower α-ketoglutarate (α-KG) in MPN patients. Inhibition of PI3K/AKT/mTOR signaling significantly reduced metabolic responses and …

Ketosis Prevents Abdominal Aortic Aneurysm Rupture Through C-C Chemokine Receptor Type 2 Downregulation And Enhanced Extracellular Matrix Balance, Sergio Sastriques-Dunlop, Santiago Elizondo-Benedetto, Batool Arif, Rodrigo Meade, Mohamed S Zaghloul, Hannah Luehmann, Gyu S Heo, Sean J English, Yongjian Liu, Mohamed A Zayed

2020-Current year OA Pubs

Abdominal aortic aneurysms (AAAs) are prevalent with aging, and AAA rupture is associated with increased mortality. There is currently no effective medical therapy to prevent AAA rupture. The monocyte chemoattractant protein (MCP-1)/C-C chemokine receptor type 2 (CCR2) axis critically regulates AAA inflammation, matrix-metalloproteinase (MMP) production, and extracellular matrix (ECM) stability. We therefore hypothesized that a diet intervention that can modulate CCR2 axis may therapeutically impact AAA risk of rupture. Since ketone bodies (KBs) can trigger repair mechanisms in response to inflammation, we evaluated whether systemic ketosis in vivo could reduce CCR2 and AAA progression. Male Sprague-Dawley rats underwent surgical AAA …

Sensory Neurons Promote Immune Homeostasis In The Lung, Masato Tamari, Aaron M Ver Heul, Masato Hoshi, Anna M Trier, Ting-Lin Yang, Sanjay Jain, Steven Van Dyken, Et Al.

2020-Current year OA Pubs

Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1

A Distinct Human Cell Type Expressing Mhcii And Rorγt With Dual Characteristics Of Dendritic Cells And Type 3 Innate Lymphoid Cells, Alina Ulezko Antonova, Changxu Fan, Natalia Jaeger, Patrick Fernandes Rodrigues, Simone Brioschi, Tihana Trsan, José L Fachi, Khai M Nguyen, Ryan M Nunley, Ting Wang, Marina Cella, William Vermi, Marco Colonna, Et Al.

2020-Current year OA Pubs

Recent studies have characterized various mouse antigen-presenting cells (APCs) expressing the lymphoid-lineage transcription factor RORγt (Retinoid-related orphan receptor gamma t), which exhibit distinct phenotypic features and are implicated in the induction of peripheral regulatory T cells (Tregs) and immune tolerance to microbiota and self-antigens. These APCs encompass Janus cells and Thetis cell subsets, some of which express the AutoImmune REgulator (AIRE). RORγt

Dna Methylation-Mediated Rbpjk Suppression Protects Against Fracture Nonunion Caused By Systemic Inflammation, Ding Xiao, Liang Fang, Zhongting Liu, Yonghua He, Jun Ying, Haocheng Qin, Aiwu Lu, Meng Shi, Tiandao Li, Bo Zhang, Jianjun Guan, Cuicui Wang, Yousef Abu-Amer, Jie Shen

2020-Current year OA Pubs

Challenging skeletal repairs are frequently seen in patients experiencing systemic inflammation. To tackle the complexity and heterogeneity of the skeletal repair process, we performed single-cell RNA sequencing and revealed that progenitor cells were one of the major lineages responsive to elevated inflammation and this response adversely affected progenitor differentiation by upregulation of Rbpjk in fracture nonunion. We then validated the interplay between inflammation (via constitutive activation of Ikk2, Ikk2ca) and Rbpjk specifically in progenitors by using genetic animal models. Focusing on epigenetic regulation, we identified Rbpjk as a direct target of Dnmt3b. Mechanistically, inflammation decreased Dnmt3b expression in progenitor cells, …

Gut Microbiota Induces Weight Gain And Inflammation In The Gut And Adipose Tissue Independent Of Manipulations In Diet, Genetics, And Immune Development, Devesha H Kulkarni, Brigida Rusconi, Alexandria N Floyd, Elisabeth L Joyce, Khushi B Talati, Hrishi Kousik, Dereck Alleyne, Dalia L Harris, Lorena Garnica, Ryan Mcdonough, Shay S Bidani, Hrishikesh S Kulkarni, Elizabeth P Newberry, Keely G Mcdonald, Rodney D Newberry

2020-Current year OA Pubs

Obesity and the metabolic syndrome are complex disorders resulting from multiple factors including genetics, diet, activity, inflammation, and gut microbes. Animal studies have identified roles for each of these, however the contribution(s) specifically attributed to the gut microbiota remain unclear, as studies have used combinations of genetically altered mice, high fat diet, and/or colonization of germ-free mice, which have an underdeveloped immune system. We investigated the role(s) of the gut microbiota driving obesity and inflammation independent of manipulations in diet and genetics in mice with fully developed immune systems. We demonstrate that the human obese gut microbiota alone was sufficient …

Blockade Of Il-6r Prevents Preterm Birth And Adverse Neonatal Outcomes, Marcelo Farias-Jofre, Valeria Garcia-Flores, Nardhy Gomez-Lopez, Et Al.

2020-Current year OA Pubs

BACKGROUND: Preterm birth preceded by spontaneous preterm labour often occurs in the clinical setting of sterile intra-amniotic inflammation (SIAI), a condition that currently lacks treatment.

METHODS: Proteomic and scRNA-seq human data were analysed to evaluate the role of IL-6 and IL-1α in SIAI. A C57BL/6 murine model of SIAI-induced preterm birth was developed by the ultrasound-guided intra-amniotic injection of IL-1α. The blockade of IL-6R by using an aIL-6R was tested as prenatal treatment for preterm birth and adverse neonatal outcomes. QUEST-MRI evaluated brain oxidative stress in utero. Targeted transcriptomic profiling assessed maternal, foetal, and neonatal inflammation. Neonatal biometrics and neurodevelopment …

Dysregulated Cd200-Cd200r Signaling In Early Diabetes Modulates Microglia-Mediated Retinopathy, Charles W Pfeifer, James T Walsh, Andrea Santeford, Joseph B Lin, Wandy L Beatty, Ryo Terao, Yizhou A Liu, Keitaro Hase, Philip A Ruzycki, Rajendra S Apte

2020-Current year OA Pubs

Diabetic retinopathy (DR) is a neurovascular complication of diabetes. Recent investigations have suggested that early degeneration of the neuroretina may occur prior to the appearance of microvascular changes; however, the mechanisms underlying this neurodegeneration have been elusive. Microglia are the predominant resident immune cell in the retina and adopt dynamic roles in disease. Here, we show that ablation of retinal microglia ameliorates visual dysfunction and neurodegeneration in a type I diabetes mouse model. We also provide evidence of enhanced microglial contact and engulfment of amacrine cells, ultrastructural modifications, and transcriptome changes that drive inflammation and phagocytosis. We show that CD200-CD200R …

Infection And Inflammation Stimulate Expansion Of A Cd74+ Paneth Cell Subset To Regulate Disease Progression, Iyshwarya Balasubramanian, Shengxiang Sun, Ta-Chiang Liu, Et Al.

2020-Current year OA Pubs

Paneth cells (PCs), a specialized secretory cell type in the small intestine, are increasingly recognized as having an essential role in host responses to microbiome and environmental stresses. Whether and how commensal and pathogenic microbes modify PC composition to modulate inflammation remain unclear. Using newly developed PC-reporter mice under conventional and gnotobiotic conditions, we determined PC transcriptomic heterogeneity in response to commensal and invasive microbes at single cell level. Infection expands the pool of CD74

T Cell Control Of Inflammaging, Irina Shchukina, Pavla Bohacova, Maxim N Artyomov

2020-Current year OA Pubs

T cells are a critical component of the immune system, found in abundance in blood, secondary lymphoid organs, and peripheral tissues. As individuals age, T cells are particularly susceptible to changes, making them one of the most affected immune subsets. These changes can have significant implications for age-related dysregulations, including the development of low-grade inflammation - a hallmark of aging known as inflammaging. In this review, we first present age-related changes in the functionality of the T cell compartment, including dysregulation of cytokine and chemokine production and cytotoxicity. Next, we discuss how these changes can contribute to the development and …

Early Resveratrol Treatment Mitigates Joint Degeneration And Dampens Pain In A Mouse Model Of Pseudoachondroplasia (Psach), Jacqueline T Hecht, Alka C Veerisetty, Debabrata Patra, Mohammad G Hossain, Frankie Chiu, Claire Mobed, Francis H Gannon, Karen L Posey

2020-Current year OA Pubs

Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 …

Multivariate Gwas Of Alzheimer's Disease Csf Biomarker Profiles Implies Grin2d In Synaptic Functioning, Alexander Neumann, Jigyasha Timsina, Thomas W Marsh, Priyanka Gorijala, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

BACKGROUND: Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences.

METHODS: We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD …

Reduction Of Sparc Protects Mice Against Nlrp3 Inflammasome Activation And Obesity, Seungjin Ryu, Olga Spadaro, Sviatoslav Sidorov, Aileen H. Lee, Sonia Caprio, Christopher Morrison, Steven R. Smith, Eric Ravussin, Irina Shchukina, Maxim N. Artyomov, Yun-Hee Youm, Vishwa Deep Dixit

2020-Current year OA Pubs

The comprehensive assessment of long-term effects of reducing intake of energy (CALERIE-II; NCT00427193) clinical trial established that caloric restriction (CR) in humans lowers inflammation. The identity and mechanism of endogenous CR-mimetics that can be deployed to control obesity-associated inflammation and diseases are not well understood. Our studies have found that 2 years of 14% sustained CR in humans inhibits the expression of the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), in adipose tissue. In mice, adipose tissue remodeling caused by weight loss through CR and low-protein diet feeding decreased, while high-fat diet-induced (HFD-induced) obesity increased SPARC expression …

Neuroinflammation In The Amygdala Is Associated With Recent Depressive Symptoms, Wei Zhang, Jerrel Rutlin, Sarah A Eisenstein, Yong Wang, Deanna M Barch, Tamara Hershey, Ryan Bogdan, Janine D Bijsterbosch

2020-Current year OA Pubs

BACKGROUND: Converging evidence suggests that elevated inflammation may contribute to depression. Yet, the link between peripheral inflammation and neuroinflammation in depression is unclear. Here, using data from the UK Biobank, we estimated associations among depression, C-reactive protein (CRP) as a measure of peripheral inflammation, and neuroinflammation as indexed by diffusion basis spectral imaging-based restricted fraction (DBSI-RF).

METHODS: DBSI-RF was derived from diffusion-weighted imaging data (N = 11,512) for whole-brain gray matter (global-RF), and regions of interest in the bilateral amygdala (amygdala-RF) and hippocampus (hippocampus-RF), and CRP was estimated from blood (serum) samples. Self-reported recent depression symptoms were measured using a …

Ube4a Maintains Metabolic Homeostasis And Facilitates Insulin Signaling In Vivo, Sandip Mukherjee, Andrew J Lutkewitte, Brian N Finck, Et Al.

2020-Current year OA Pubs

OBJECTIVE: Defining the regulators of cell metabolism and signaling is essential to design new therapeutic strategies in obesity and NAFLD/NASH. E3 ubiquitin ligases control diverse cellular functions by ubiquitination-mediated regulation of protein targets, and thus their functional aberration is associated with many diseases. The E3 ligase Ube4A has been implicated in human obesity, inflammation, and cancer. However, its in vivo function is unknown, and no animal models are available to study this novel protein.

METHODS: A whole-body Ube4A knockout (UKO) mouse model was generated, and various metabolic parameters were compared in chow- and high fat diet (HFD)-fed WT and UKO …

Loss Of Stearoyl-Coa Desaturase 2 Disrupts Inflammatory Response In Macrophages, Joseph B. Lin, Amy Mora, Tzu Jui Wang, Andrea Santeford, Darksha Usmani, Marianne M. Ligon, Indira U. Mysorekar, Rajendra S. Apte

2020-Current year OA Pubs

Macrophages are innate immune cells that patrol tissues and are the first responders to detect infection. They orchestrate the host immune response in eliminating invading pathogens and the subsequent transition from inflammation to tissue repair. Macrophage dysfunction contributes to age-related pathologies, including low-grade inflammation in advanced age that is termed "inflammaging." Our laboratory has previously identified that macrophage expression of a fatty acid desaturase, stearoyl-CoA desaturase 2 (SCD2), declines with age. Herein, we delineate the precise cellular effects of SCD2 deficiency in murine macrophages. We found that deletion of

Microglial Rev-Erbα Regulates Inflammation And Lipid Droplet Formation To Drive Tauopathy In Male Mice, Jiyeon Lee, Julie M Dimitry, Jong Hee Song, Minsoo Son, Patrick W Sheehan, Melvin W King, G Travis Tabor, Young Ah Goo, Mitchell A Lazar, Leonard Petrucelli, Erik S Musiek

2020-Current year OA Pubs

Alzheimer's disease, the most common age-related neurodegenerative disease, is characterized by tau aggregation and associated with disrupted circadian rhythms and dampened clock gene expression. REV-ERBα is a core circadian clock protein which also serves as a nuclear receptor and transcriptional repressor involved in lipid metabolism and macrophage function. Global REV-ERBα deletion has been shown to promote microglial activation and mitigate amyloid plaque formation. However, the cell-autonomous effects of microglial REV-ERBα in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male …

Histidine-Rich Protein Ii Nanoparticle Delivery Of Heme Iron Load Drives Endothelial Inflammation In Cerebral Malaria, Suong T Nguyen, Daniel Du, Daniel Wychrij, Matthew D Cain, Qingping Wu, Robyn S Klein, Ilaria Russo, Daniel E Goldberg

2020-Current year OA Pubs

Histidine-rich protein II (HRPII) is secreted by

Antigen-Driven Colonic Inflammation Is Associated With Development Of Dysplasia In Primary Sclerosing Cholangitis, Dustin G Shaw, Kelly Monroe, Rodney Newberry, Et Al.

2020-Current year OA Pubs

Primary sclerosing cholangitis (PSC) is an immune-mediated disease of the bile ducts that co-occurs with inflammatory bowel disease (IBD) in almost 90% of cases. Colorectal cancer is a major complication of patients with PSC and IBD, and these patients are at a much greater risk compared to patients with IBD without concomitant PSC. Combining flow cytometry, bulk and single-cell transcriptomics, and T and B cell receptor repertoire analysis of right colon tissue from 65 patients with PSC, 108 patients with IBD and 48 healthy individuals we identified a unique adaptive inflammatory transcriptional signature associated with greater risk and shorter time …

Basal Type I Interferon Signaling Has Only Modest Effects On Neonatal And Juvenile Hematopoiesis, Yanan Li, Wei Yang, Helen C Wang, Riddhi M Patel, Emily B Casey, Elisabeth Denby, Jeffrey A Magee

2020-Current year OA Pubs

Type I interferon (IFN-1) regulates gene expression and hematopoiesis both during development and in response to inflammatory stress. We previously showed that during development in mice, hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) induce IFN-1 target genes shortly before birth. This coincides with the onset of a transition to adult hematopoiesis, and it drives the expression of genes associated with antigen presentation. However, it is not clear whether perinatal IFN-1 modulates hematopoietic output, as has been observed in contexts of inflammation. We have characterized hematopoiesis at several different stages of blood formation, from HSCs to mature blood cells, and …

Intrinsic Tgf-Β Signaling Attenuates Proximal Tubule Mitochondrial Injury And Inflammation In Chronic Kidney Disease, Merve Kayhan, Judith Vouillamoz, Daymé Gonzalez Rodriguez, Milica Bugarski, Yasutaka Mitamura, Julia Gschwend, Christoph Schneider, Andrew Hall, David Legouis, Cezmi A Akdis, Leary Peter, Hubert Rehrauer, Leslie Gewin, Roland H Wenger, Stellor Nlandu Khodo

2020-Current year OA Pubs

Excessive TGF-β signaling and mitochondrial dysfunction fuel chronic kidney disease (CKD) progression. However, inhibiting TGF-β failed to impede CKD in humans. The proximal tubule (PT), the most vulnerable renal segment, is packed with giant mitochondria and injured PT is pivotal in CKD progression. How TGF-β signaling affects PT mitochondria in CKD remained unknown. Here, we combine spatial transcriptomics and bulk RNAseq with biochemical analyses to depict the role of TGF-β signaling on PT mitochondrial homeostasis and tubulo-interstitial interactions in CKD. Male mice carrying specific deletion of Tgfbr2 in the PT have increased mitochondrial injury and exacerbated Th1 immune response in …

Autophagy Prevents Early Proinflammatory Responses And Neutrophil Recruitment During Mycobacterium Tuberculosis Infection Without Affecting Pathogen Burden In Macrophages, Rachel L. Kinsella, Jacqueline M. Kimmey, Asya Smirnov, Reilly Woodson, Margaret R. Gaggioli, Sthefany M. Chavez, Darren Kreamalmeyer, Christina L. Stallings

2020-Current year OA Pubs

The immune response to Mycobacterium tuberculosis infection determines tuberculosis disease outcomes, yet we have an incomplete understanding of what immune factors contribute to a protective immune response. Neutrophilic inflammation has been associated with poor disease prognosis in humans and in animal models during M. tuberculosis infection and, therefore, must be tightly regulated. ATG5 is an essential autophagy protein that is required in innate immune cells to control neutrophil-dominated inflammation and promote survival during M. tuberculosis infection; however, the mechanistic basis for how ATG5 regulates neutrophil recruitment is unknown. To interrogate what innate immune cells require ATG5 to control neutrophil recruitment …

Involucrin Modulates Vitamin D Receptor Activity In The Epidermis, Alina D Schmidt, Charlene Miciano, Qi Zheng, Mary Elizabeth Mathyer, Elizabeth A Grice, Cristina De Guzman Strong

2020-Current year OA Pubs

Terminally differentiated keratinocytes are critical for epidermal function and are surrounded by involucrin (IVL). Increased IVL expression is associated with a near-selective sweep in European populations compared with those in Africa. This positive selection for increased IVL in the epidermis identifies human adaptation outside of Africa. The functional significance is unclear. We hypothesize that IVL modulates the environmentally sensitive vitamin D receptor (VDR) in the epidermis. We investigated VDR activity in Ivl

Immunotherapeutic Approach To Reduce Senescent Cells And Alleviate Senescence-Associated Secretory Phenotype In Mice, Niraj Shrestha, Mark Foster, Lynne Marsala, Pamela Wong, Celia C Cubitt, Jennifer A Foltz, Jennifer Tran, Timothy Schappe, Melissa M Berrien-Elliott, Todd A Fehniger, Et Al.

2020-Current year OA Pubs

Accumulation of senescent cells (SNCs) with a senescence-associated secretory phenotype (SASP) has been implicated as a major source of chronic sterile inflammation leading to many age-related pathologies. Herein, we provide evidence that a bifunctional immunotherapeutic, HCW9218, with capabilities of neutralizing TGF-β and stimulating immune cells, can be safely administered systemically to reduce SNCs and alleviate SASP in mice. In the diabetic db/db mouse model, subcutaneous administration of HCW9218 reduced senescent islet β cells and SASP resulting in improved glucose tolerance, insulin resistance, and aging index. In naturally aged mice, subcutaneous administration of HCW9218 durably reduced the level of SNCs and …

Simultaneous Inhibition Of Thrombosis And Inflammation Is Beneficial In Treating Acute Myocardial Infarction, Ian Vargas, Ryan P Grabau, Junjie Chen, Carla Weinheimer, Attila Kovacs, William Dominguez-Viqueira, Adam Mitchell, Samuel A Wickline, Hua Pan

2020-Current year OA Pubs

Myocardial ischemia reperfusion injury (IRI) in acute coronary syndromes is a condition in which ischemic/hypoxic injury to cells subtended by the occluded vessel continues despite successful resolution of the thrombotic obstruction. For decades, most efforts to attenuate IRI have focused on interdicting singular molecular targets or pathways, but none have successfully transitioned to clinical use. In this work, we investigate a nanoparticle-based therapeutic strategy for profound but local thrombin inhibition that may simultaneously mitigate both thrombosis and inflammatory signaling pathways to limit myocardial IRI. Perfluorocarbon nanoparticles (PFC NP) were covalently coupled with an irreversible thrombin inhibitor, PPACK (Phe[D]-Pro-Arg-Chloromethylketone), and delivered …

Nadph Oxidase 2 Limits Amplification Of Il-1Β-G-Csf Axis And An Immature Neutrophil Subset In Murine Lung Inflammation, Zhimin Song, Sourav Bhattacharya, Guangming Huang, Zev J Greenberg, Wei Yang, Juhi Bagaitkar, Laura G Schuettpelz, Mary C Dinauer

2020-Current year OA Pubs

The leukocyte NADPH oxidase 2 (NOX2) regulates inflammation independent of its antimicrobial activity. Inherited defects in NOX2 lead to chronic granulomatous disease (CGD), associated with recurrent bacterial and fungal infections, often with excessive neutrophilic inflammation that results in significant inflammatory burden and tissue damage. We previously showed that excessive leukotriene B4 (LTB4) production by NOX2-deficient mouse neutrophils was a key driver of elevated lung neutrophil infiltration in the initial response to pulmonary challenge with the model fungal particle zymosan. We now identify interleukin-1β (IL-1β) and downstream granulocyte colony-stimulating factor (G-CSF) as critical amplifying signals that augment and sustain neutrophil accrual …

The Tetraspanin Transmembrane Protein Cd53 Mediates Dyslipidemia And Integrates Inflammatory And Metabolic Signaling In Hepatocytes, Cassandra B Higgins, Joshua A Adams, Matthew H Ward, Zev J Greenberg, Małgorzata Milewska, Jiameng Sun, Yiming Zhang, Luana Chiquetto Paracatu, Qian Dong, Samuel Ballentine, Weikai Li, Ilona Wandzik, Laura G Schuettpelz, Brian J Debosch

2020-Current year OA Pubs

Tetraspanins are transmembrane signaling and proinflammatory proteins. Prior work demonstrates that the tetraspanin, CD53/TSPAN25/MOX44, mediates B-cell development and lymphocyte migration to lymph nodes and is implicated in various inflammatory diseases. However, CD53 is also expressed in highly metabolic tissues, including adipose and liver; yet its function outside the lymphoid compartment is not defined. Here, we show that CD53 demarcates the nutritional and inflammatory status of hepatocytes. High-fat exposure and inflammatory stimuli induced CD53 in vivo in liver and isolated primary hepatocytes. In contrast, restricting hepatocyte glucose flux through hepatocyte glucose transporter 8 deletion or through trehalose treatment blocked CD53 induction …