Gyarmati et al. identify the central roles of glomerular mechanical forces as well as endothelial and immune cell activation early in Alport syndrome. The cover image shows intravital multiphoton microscopy imaging of immune cell features in a late-stage Alport syndrome model.
Impaired glucose metabolism is observed in obesity and type 2 diabetes. Glucose controls gene expression through the transcription factor ChREBP in liver and adipose tissues. Mlxipl encodes two isoforms, ChREBPα, the full-length form which translocation into the nucleus is under the control of glucose and, ChREBPβ, a constitutively nuclear shorter form. ChREBPβ gene expression in white adipose tissue is strongly associated with insulin sensitivity. Here, we investigated the consequences of ChREBPβ deficiency on insulin action and energy balance. ChREBPβ-deficient male and female C57BL6/J and FVB/N mice were produced using CRISPR-Cas9-mediated gene editing. Unlike global ChREBP deficiency, lack of ChREBPβ showed modest effects on gene expression in adipose tissues and liver, with variations seen chiefly in brown adipose tissue. In mice fed chow and high fat diets, lack of ChREBPβ had moderate effects on body composition and insulin sensitivity. ChREBPβ deficiency did not prevent the whitening of brown adipose tissue reported in total ChREBP knock out mice at thermoneutrality. These findings reveal that ChREBPβ is dispensable for metabolic adaptations to nutritional and thermic challenges.
Emeline Recazens, Geneviève Tavernier, Jérémy Dufau, Camille Bergoglio, Fadila Benhamed, Stéphanie Cassant-Sourdy, Marie-Adeline Marques, Sylvie Caspar-Bauguil, Alice Brion, Laurent Monbrun, Renaud Dentin, Clara Ferrier, Mélanie Leroux, Pierre-Damien Denechaud, Cedric Moro, Jean-Paul Concordet, Catherine Postic, Etienne Mouisel, Dominique Langin
Total body irradiation (TBI) targets sensitive bone marrow hematopoietic cells and gut epithelial cells causing their death and TBI induces the state of immunodeficiency combined with intestinal dysbiosis and non-productive immune responses. We found enhanced Pseudomonas aeruginosa (PA) colonization of the gut leading to the host cell death and strikingly decreased survival of irradiated mice. PA-driven pathogenic mechanism includes theft-ferroptosis is realized via: i) curbing host anti-ferroptotic system GSH/GPx4 and ii) employing bacterial 15-lipoxygenase (pLoxA) to generate pro-ferroptotic signal - 15-hyderoperoxy-arachidonyl-PE (15-HpETE-PE) - in the intestines of irradiated/infected mice. Global redox phospholipidomics of the ileum revealed that lyso-phospholipids and oxidized phospholipids (particularly PEox) represented the major factors which contributed to the TBI+PA induced pathogenic changes. A lipoxygenase inhibitor, baicalein, significantly attenuated animal lethality, PA colonization, as well as intestinal epithelial cell death and generation of ferroptotic PEox signals. Opportunistic PA mechanisms included stimulation of the anti-inflammatory lipoxin A4 (LXA4) production and suppression of the pro-inflammatory hepoxilin A3 (HxA3) and leukotriene B4 (LTB4). Unearthing complex PA pathogenic/virulence mechanisms including effects on the host anti-/pro-inflammatory responses, lipid metabolism and ferroptotic cell death points to new therapeutic and radiomitigative targets.
Haider H. Dar, Michael W. Epperly, Vladimir A. Tyurin, Andrew A. Amoscato, Tamil S. Anthonymuthu, Austin B. Souryavong, Alexander A. Kapralov, Galina V. Shurin, Svetlana N. Samovich, Claudette M. St. Croix, Simon C. Watkins, Sally E. Wenzel, Rama K. Mallampalli, Joel S. Greenberger, Hulya Bayir, Valerian E. Kagan, Yulia Y. Tyurina
Defective primary cilia cause a range of diseases called ciliopathies, which include hearing loss (HL). Variants in human oxysterol binding protein like 2 (OSBPL2/ORP2) are responsible for autosomal dominant nonsyndromic HL (DFNA67). However, the pathogenesis of OSBPL2 deficiency has not been fully elucidated. In this study, we showed that the Osbpl2-knockout (KO) mice exhibited progressive HL and abnormal cochlea development with defective cilia. Further research revealed that OSBPL2 was located at the base of kinocilia in hair cells (HCs) and primary cilia in supporting cells (SCs), and functioned in the maintenance of ciliogenesis by regulating the homeostasis of PI(4,5)P2 on the cilia membrane. OSBPL2 deficiency led to a significant increase of PI(4,5)P2 on the cilia membrane, which could be partially rescued by the overexpression of INPP5E. In addition, the key molecules in Sonic Hedgehog (Shh) signaling pathway (SMO and GLI3) were detected to be down-regulated in Osbpl2-KO HEI-OC1 cells. Our findings revealed that OSBPL2 deficiency resulted in ciliary defects and abnormal Shh signaling transduction in auditory cells, which helped to elucidate the underlying mechanism of OSBPL2 deficiency in HL.
Hairong Shi, Hongshun Wang, Cheng Zhang, Yajie Lu, Jun Yao, Zhibin Chen, Guangqian Xing, Qinjun Wei, Xin Cao
BACKGROUND. Vaccine-elicited adaptive immunity is a prerequisite for control of SARS-CoV-2 infection. Multiple sclerosis (MS) disease-modifying therapies (DMTs) differentially target humoral and cellular immunity. A comprehensive comparison of MS DMTs on SARS-CoV-2 vaccine-specific immunity is needed, including quantitative and functional B and T cell responses. METHODS. Spike-specific antibody and T cell responses were measured before and following SARS-CoV-2 vaccination in a cohort of 80 subjects, including healthy controls and MS patients in six DMT groups: untreated, glatiramer acetate (GA), dimethyl fumarate (DMF), natalizumab (NTZ), sphingosine-1-phosphate (S1P) receptor modulators, and anti-CD20 monoclonal antibodies. Anti-spike antibody responses were quantified by Luminex assay, high-resolution spike epitope reactivity was mapped by VirScan, and pseudovirus neutralization was assessed. Spike-specific CD4+ and CD8+ T cell responses were characterized by activation-induced marker (AIM) expression, cytokine production, and tetramer analysis. RESULTS. Anti-spike IgG levels were similar between healthy controls, untreated MS, GA, DMF, and NTZ patients, but were significantly reduced in anti-CD20 and S1P-treated patients. Anti-spike seropositivity in anti-CD20 patients was significantly correlated with CD19+ B cell levels and inversely correlated with cumulative treatment duration. Spike epitope reactivity and pseudovirus neutralization was reduced in anti-CD20 and S1P patients, directly correlating with reduced spike receptor binding domain (RBD) IgG levels. Spike-specific CD4+ and CD8+ T cell reactivity remained robust across all groups except in S1P-treated patients in whom post-vaccine CD4+ T cell responses were attenuated. CONCLUSIONS. These findings from a large MS cohort exposed to a wide spectrum of MS immunotherapies have important implications for treatment-specific COVID-19 clinical guidelines. FUNDING. This work was supported by grants from the NIH 1K08NS107619 (JJS), NMSS TA- 1903-33713 (JJS), K08NS096117 (MRW), Westridge Foundation (MRW), Chan Zuckerberg Biohub (JLD), R01AI159260 (JAH), R01NS092835 (SSZ), R01AI131624 (SSZ), R21NS108159 (SSZ), NMSS RG1701-26628 (SSZ), and the Maisin Foundation (SSZ).
Joseph J. Sabatino Jr, Kristen Mittl, William M. Rowles, Kira McPolin, Jayant V. Rajan, Matthew T. Laurie, Colin R. Zamecnik, Ravi Dandekar, Bonny D. Alvarenga, Rita P. Loudermilk, Chloe Gerungan, Collin M. Spencer, Sharon A. Sagan, Danillo G. Augusto, Jessa R. Alexander, Joseph L. DeRisi, Jill A. Hollenbach, Michael R. Wilson, Scott S. Zamvil, Riley Bove
Aristolochic acid (AA) is the causative nephrotoxic alkaloid in aristolochic acid nephropathy, which results in a tubulointerstitial fibrosis. AA causes direct proximal tubule damage. There is also an influx of macrophages, although their role in the pathogenesis is poorly understood. Here we demonstrate that AA directly stimulates migration, inflammation, and reactive oxygen species (ROS) production in macrophages ex vivo. Cells lacking interferon regulatory factor 4 (IRF4), a known regulator of macrophage migration and phenotype, had a reduced migratory response, though effects on ROS production and inflammation were preserved or increased relative to wild-type cells. Macrophage-specific IRF4 knockout mice were protected from both acute and chronic kidney effects of AA administration based on functional and histological analysis. Renal macrophages from kidneys of AA-treated macrophage-specific IRF4 knockout mice demonstrated increased apoptosis and ROS production compared with wildtype controls, indicating that AA directly polarizes macrophages to a promigratory and proinflammatory phenotype. However, knockout mice had reduced renal macrophage abundance following AA administration. While macrophages lacking IRF4 can adopt a proinflammatory phenotype upon AA exposure, their inability to migrate to the kidney and increased rates of apoptosis upon infiltration provide protection from AA in vivo. These results provide evidence of direct AA effects on macrophages in AAN and add to the growing body of evidence that supports a key role of IRF4 in modulating macrophage function in kidney injury.
Kensuke Sasaki, Andrew S. Terker, Jiaqi Tang, Shirong Cao, Juan Pablo Arroyo, Aolei Niu, Suwan Wang, Xiaofeng Fan, Yahua Zhang, Stephanie R. Bennett, Ming-zhi Zhang, Raymond C. Harris
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