bims-nimamd 2021-11-28 papers

bims-nimamd

Biomed News

on Neuroimmunity and neuroinflammation in ageing and metabolic disease

Issue of 2021–11–28
nineteen papers selected by
Fawaz Alzaïd, Sorbonne Université

Invariant NKT Cells Promote the Development of Highly Cytotoxic Multipotent CXCR3+CCR4+CD8+ T Cells That Mediate Rapid Hepatocyte Allograft Rejection.
Fatty acid metabolism in adaptive immunity.
Deletion of ABCB10 in beta-cells protects from high-fat diet induced insulin resistance.
From mapping kidney function to mechanism and prediction.
Long noncoding RNAs associated with nonalcoholic fatty liver disease in a high cholesterol diet adult zebrafish model.
Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity.
Identification of Non-classical Follicular T Cells.
The pathogenic role of IFN-α in thyroiditis mouse models.
CORTISTATIN REGULATES FIBROSIS AND MYOFIBROBLAST ACTIVATION IN EXPERIMENTAL HEPATOTOXIC- AND CHOLESTATIC-INDUCED LIVER INJURY.
Accumulation of Senescent Neural Cells in Murine Lupus With Depression-Like Behavior.
The Immunomodulatory Functions of Butyrate.
Nanoparticle-Induced Airway Eosinophilia Is Independent of ILC2 Signaling but Associated With Sex Differences in Macrophage Phenotype Development.
Resident and migratory adipose immune cells control systemic metabolism and thermogenesis.
High-Resolution Exposomics and Metabolomics Reveals Specific Associations in Cholestatic Liver Diseases.
Novel humanized-PBMC mouse model with delayed onset of GVHD for preclinical HIV research.
Bile acids contribute to the development of non-alcoholic steatohepatitis in mice.
Resolving macrophage polarization through distinct Ca2+ entry channel that maintains intracellular signaling and mitochondrial bioenergetics.
Stereotypic Expansion of T Regulatory and Th17 Cells during Infancy Is Disrupted by HIV Exposure and Gut Epithelial Damage.
Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation.

J Immunol. 2021 Nov 22. pii: ji2100334. [Epub ahead of print]

Invariant NKT Cells Promote the Development of Highly Cytotoxic Multipotent CXCR3+CCR4+CD8+ T Cells That Mediate Rapid Hepatocyte Allograft Rejection.

Jason M Zimmerer, Bryce A Ringwald, Sachi R Chaudhari, Jing Han, Chelsea M Peterson, Robert T Warren, Madison M Hart, Mahmoud Abdel-Rasoul, Ginny L Bumgardner.

Hepatocyte transplant represents a treatment for metabolic disorders but is limited by immunogenicity. Our prior work identified the critical role of CD8+ T cells, with or without CD4+ T cell help, in mediating hepatocyte rejection. In this study, we evaluated the influence of invariant NKT (iNKT) cells, uniquely abundant in the liver, upon CD8-mediated immune responses in the presence and absence of CD4+ T cells. To investigate this, C57BL/6 (wild-type) and iNKT-deficient Jα18 knockout mice (cohorts CD4 depleted) were transplanted with allogeneic hepatocytes. Recipients were evaluated for alloprimed CD8+ T cell subset composition, allocytotoxicity, and hepatocyte rejection. We found that CD8-mediated allocytotoxicity was significantly decreased in iNKT-deficient recipients and was restored by adoptive transfer of iNKT cells. In the absence of both iNKT cells and CD4+ T cells, CD8-mediated allocytotoxicity and hepatocyte rejection was abrogated. iNKT cells enhance the proportion of a novel subset of multipotent, alloprimed CXCR3+CCR4+CD8+ cytolytic T cells that develop after hepatocyte transplant and are abundant in the liver. Alloprimed CXCR3+CCR4+CD8+ T cells express cytotoxic effector molecules (perforin/granzyme and Fas ligand) and are distinguished from alloprimed CXCR3+CCR4-CD8+ T cells by a higher proportion of cells expressing TNF-α and IFN-γ. Furthermore, alloprimed CXCR3+CCR4+CD8+ T cells mediate higher allocytotoxicity and more rapid allograft rejection. Our data demonstrate the important role of iNKT cells in promoting the development of highly cytotoxic, multipotent CXCR3+CCR4+CD8+ T cells that mediate rapid rejection of allogeneic hepatocytes engrafted in the liver. Targeting iNKT cells may be an efficacious therapy to prevent rejection of intrahepatic cellular transplants.

DOI: https://doi.org/10.4049/jimmunol.2100334
FEBS J. 2021 Nov 25.

Fatty acid metabolism in adaptive immunity.

Xian Zhou, Xingxing Zhu, Hu Zeng.

  Fatty acids not only are a key component of cellular membrane structure, but also have diverse functions in biological processes. Recent years have seen great advances in understanding of how fatty acid metabolism contributes to adaptive immune response. Here, we review 3 key processes, fatty acid biosynthesis, fatty acid oxidation and fatty acid uptake, and how they direct T and B cell functions during immune challenges. Then we will focus on the relationship between microbiota derived fatty acids, short-chain fatty acids, and adaptive immunity. Along the way, we will also discuss the outstanding controversies and challenges in the field.

Keywords:  B cells; Fatty acid; T cells; Treg; germinal center; memory; mitochondrial; oxidation

DOI:  https://doi.org/10.1111/febs.16296
Mol Metab. 2021 Nov 22. pii: S2212-8778(21)00261-1. [Epub ahead of print] 101403

Deletion of ABCB10 in beta-cells protects from high-fat diet induced insulin resistance.

Michael Shum, Mayuko Segawa, Raffi Gharakhanian, Ana Viñuela, Matthew Wortham, Siyouneh Baghdasarian, Dane M Wolf, Samuel B Sereda, Laura Nocito, Linsey Stiles, Zhiqiang Zhou, Vincent Gutierrez, Maike Sander, Orian S Shirihai, Marc Liesa.

   AIMS: The contribution of beta-cell dysfunction to type 2 diabetes (T2D) is not restricted to insulinopenia in the late stages of the disease. Elevated fasting insulinemia in normoglycemic humans is a major factor predicting the onset of insulin resistance and T2D, demonstrating an early alteration of beta-cell function in T2D. Moreover, an early and chronic increase in fasting insulinemia contributes to insulin resistance in high-fat diet (HFD) fed mice. However, whether genetic factors exist that promote beta-cell initiated insulin resistance remains undefined. Human variants of the mitochondrial transporter ABCB10, which regulates redox by increasing bilirubin synthesis, are associated with elevated T2D risk. The effects of T2D ABCB10 variants on ABCB10 expression and the actions of ABCB10 in beta-cells are unknown.
METHODS: Beta-cell ABCB10 expression was analyzed in published transcriptome datasets from human beta-cells carrying the T2D-risk ABCB10 variant. Insulin sensitivity, beta-cell proliferation and secretory function were measured in beta-cell specific ABCB10 KO mice (Ins1Cre-Abcb10flox/flox). The short-term role of beta-cell ABCB10 activity on glucose-stimulated insulin secretion (GSIS) was determined in isolated islets.
RESULTS: Carrying the T2D risk allele G of ABCB10 rs348330 variant was associated with increased ABCB10 expression in human beta-cells. Constitutive deletion of Abcb10 in beta-cells protected mice from hyperinsulinemia and insulin resistance, by limiting HFD-induced beta-cell expansion. An early limitation in GSIS and H2O2-mediated signaling caused by elevated ABCB10 activity can initiate an over-compensatory expansion of beta-cell mass in response to HFD. Accordingly, increasing ABCB10 expression was sufficient to limit GSIS capacity. In health, ABCB10 protein was decreased during islet maturation, with maturation restricting beta-cell proliferation and elevating GSIS. Finally, ex-vivo and short-term deletion of Abcb10 in islets isolated from HFD-fed mice increased H2O2 and GSIS, which was reversed by bilirubin treatments.
CONCLUSIONS: Beta-cell ABCB10 is required for HFD to induce insulin resistance in mice, by amplifying beta-cell mass expansion to maladaptive levels that cause fasting hyperinsulinemia.

Keywords:  ABCB10; beta-cell; insulin resistance; mitochondria

DOI:  https://doi.org/10.1016/j.molmet.2021.101403
Nat Rev Nephrol. 2021 Nov 24.

From mapping kidney function to mechanism and prediction.

Daigoro Hirohama, Katalin Susztak.

DOI: https://doi.org/10.1038/s41581-021-00512-5
Sci Rep. 2021 Nov 26. 11(1): 23005

Long noncoding RNAs associated with nonalcoholic fatty liver disease in a high cholesterol diet adult zebrafish model.

Hyo Jung An, Yoon Jung Lee, Chong Pyo Choe, Hyun-Kyung Cho, Dae Hyun Song.

The mechanism of nonalcoholic fatty liver disease (NAFLD) has not been completely revealed. In this study, we investigated the association of liver histological changes and long noncoding RNAs (lncRNAs) in the NAFLD zebrafish model. Forty zebrafish were fed a high-cholesterol diet (1.5 g per day) for 8 weeks. We measured fatty liver changes in the zebrafish liver using oil red O staining and divided them into two groups based on high and low scores. We pooled each group of zebrafish livers and identified lncRNAs, miRNAs, and mRNAs using Next-generation sequencing. Human homologs of lncRNAs were identified using ZFLNC, Ensembl, and NONCODE. We found several significant genes, including 32 lncRNAs, 5 miRNA genes, and 8 protein-coding genes, that were associated with liver metabolism and NAFLD-related functions in zebrafish. In particular, eight conserved human homologs of lncRNAs were found. We discovered the human homologs of eight lncRNA candidates from fatty liver zebrafish for the first time. The spectrum of biological mechanisms by which lncRNAs mediate their functional roles in NAFLD in a high cholesterol diet adult zebrafish model remains to be uncovered.

DOI: https://doi.org/10.1038/s41598-021-02455-0
Cell Metab. 2021 Nov 19. pii: S1550-4131(21)00530-1. [Epub ahead of print]

Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity.

Lichao Wang, Binsheng Wang, Nathan S Gasek, Yueying Zhou, Rachel L Cohn, Dominique E Martin, Wulin Zuo, William F Flynn, Chun Guo, Evan R Jellison, Taewan Kim, Larissa G P Langhi Prata, Allyson K Palmer, Ming Li, Christina L Inman, Lauren S Barber, Iman M A Al-Naggar, Yanjiao Zhou, George A Kuchel, Alexander Meves, Tamar Tchkonia, James L Kirkland, Paul Robson, Ming Xu.

  Insulin resistance is a pathological state often associated with obesity, representing a major risk factor for type 2 diabetes. Limited mechanism-based strategies exist to alleviate insulin resistance. Here, using single-cell transcriptomics, we identify a small, critically important, but previously unexamined cell population, p21Cip1 highly expressing (p21high) cells, which accumulate in adipose tissue with obesity. By leveraging a p21-Cre mouse model, we demonstrate that intermittent clearance of p21high cells can both prevent and alleviate insulin resistance in obese mice. Exclusive inactivation of the NF-κB pathway within p21high cells, without killing them, attenuates insulin resistance. Moreover, fat transplantation experiments establish that p21high cells within fat are sufficient to cause insulin resistance in vivo. Importantly, a senolytic cocktail, dasatinib plus quercetin, eliminates p21high cells in human fat ex vivo and mitigates insulin resistance following xenotransplantation into immuno-deficient mice. Our findings lay the foundation for pursuing the targeting of p21high cells as a new therapy to alleviate insulin resistance.

Keywords:  Cellular senescence; NF-κB; diabetes; fat transplantation; senolytics; xenograft

DOI:  https://doi.org/10.1016/j.cmet.2021.11.002
Methods Mol Biol. 2022 ;2380 77-84

Identification of Non-classical Follicular T Cells.

Alan Courey-Ghaouzi, Mauro Gaya.

  Nonclassical T cells are a heterogeneous group of T lymphocytes that are activated during the early stages of infection and act as a bridge between the innate and adaptive immune system. Among them, Natural Killer T (NKT) cells have been extensively studied in the last two decades due to their unique ability to recognize foreign/self-lipid antigens in the context of CD1d, a nonclassical major histocompatibility complex molecule. In this chapter, we describe our protocols to track murine NKT cells in lymph nodes by flow cytometry and confocal microscopy.

Keywords:  CD1d-tetramer; Confocal microscopy; Flow cytometry; Influenza virus; Lymph node; Natural Killer T (NKT) cells

DOI:  https://doi.org/10.1007/978-1-0716-1736-6_7
Life Sci. 2021 Nov 23. pii: S0024-3205(21)01159-0. [Epub ahead of print] 120172

The pathogenic role of IFN-α in thyroiditis mouse models.

Chao-Wen Cheng, Wen-Fang Fang, Kam-Tsun Tang, Jiunn-Diann Lin.

   AIM: Patients with chronic hepatitis C are frequently treated with interferon (IFN)-α. Autoimmune thyroid disease occurs in 20% ~ 40% of IFN-α-treated patients. In this study, the effects of IFN-α administration on triggering and regulating autoimmune thyroiditis in various animal models were evaluated.
MAIN METHODS: Exogenous IFN-α was given to naive CBA mice, and both thyroglobulin (TG) immunization-induced (CBA) and spontaneous autoimmune thyroiditis (NOD·H-2 h4) models. Thyroid function, and anti-thyroglobulin antibody (ATA) and B-cell-activating factor (BAFF) levels were measured. Alterations in transcriptome profiles were analyzed.
KEY FINDINGS: In the TG-induced thyroiditis model, IFN-α administration reduced plasma free thyroxine levels but did not alter ATA titers, BAFF levels, or the severity of histological changes. Interestingly, even without changes in thyroid functions, four of eight mice in the IFN-α alone group exhibited thyroiditis compared to the control group. Immunologically, mice in the IFN-α group exhibited profound CD3+ cell infiltration in the thyroid and higher plasma BAFF levels compared to the control group. Meanwhile, pathological and serological alterations after IFN-α administration were not observed in the NOD·H-2 h4 model. An RNA sequencing analysis revealed that immunoregulatory signatures were not excited by IFN-α treatment in naive CBA mice. Meanwhile, innate and adaptive immunity, inflammatory cytokine, chemokine, and cell-killing signaling pathways were all stimulated by IFN-α administration after TG immunization of CBA mice.
SIGNIFICANCE: We confirmed the remarkable effects of IFN-α in both initiating thyroid immunity and modulating thyroid function and immunoregulatory signatures in established autoimmune thyroiditis. We suggest that IFN-α should be administered with caution in clinical settings.

Keywords:  CBA; Interferon-α; NOD·H-2 h4; Thyroglobulin; Thyroiditis

DOI:  https://doi.org/10.1016/j.lfs.2021.120172
Br J Pharmacol. 2021 Nov 24.

CORTISTATIN REGULATES FIBROSIS AND MYOFIBROBLAST ACTIVATION IN EXPERIMENTAL HEPATOTOXIC- AND CHOLESTATIC-INDUCED LIVER INJURY.

Raquel Benitez, Marta Caro, Eduardo Andres-Leon, Francisco O'Valle, Mario Delgado.

   BACKGROUND AND PURPOSE: Liver fibrosis induced by chronic hepatic injury remains as a major cause of morbidity and mortality worldwide. Identification of susceptibility/prognosis factors and new therapeutic tools for treating hepatic fibrotic disorders are urgent medical needs. Cortistatin is a neuropeptide with potent anti-inflammatory and anti-fibrotic activities in lung that binds to receptors that are expressed in liver fibroblasts and hepatic stellate cells. We evaluated the capacity of cortistatin to regulate liver fibrosis.
EXPERIMENTAL APPROACH: We experimentally induced liver fibrosis in mice by chronic CCl4 exposition and bile duct ligation and evaluated the histopathological signs and fibrotic markers.
KEY RESULTS: Hepatic expression of cortistatin inversely correlated with liver fibrosis grade in mice and humans with hepatic disorders. Cortistatin-deficient mice showed exacerbated signs of liver damage and fibrosis and increased mortality rates when challenged to hepatotoxic and cholestatic injury. Compared to wild-type mice, non-parenchymal liver cells isolated from cortistatin-deficient mice showed increased presence of cells with activated myofibroblast phenotypes and a differential genetic signature that is indicative of activated hepatic stellate cells and periportal fibroblasts and of myofibroblasts with active contractile apparatus. Cortistatin treatment reversed in vivo and in vitro these exaggerated fibrogenic phenotypes and protected from progression to severe liver fibrosis in response to hepatic injury.
CONCLUSION AND IMPLICATIONS: We identify cortistatin as an endogenous molecular break of liver fibrosis and its deficiency as a potential poor-prognosis marker for chronic hepatic disorders that course with fibrosis. Cortistatin-based therapies emerge as attractive strategies for ameliorating severe hepatic fibrosis of various etiologies.

Keywords:  Kupffer cells; bile duct ligation; contractile fibers; hepatic stellate cell; neuropeptide; periportal fibroblast

DOI:  https://doi.org/10.1111/bph.15752
Front Immunol. 2021 ;12 692321

Accumulation of Senescent Neural Cells in Murine Lupus With Depression-Like Behavior.

Yuki Saito, Maki Miyajima, Sena Yamamoto, Tsukasa Sato, Norihiro Miura, Mineko Fujimiya, Takako S Chikenji.

  Neuropsychiatric manifestations targeting the central, peripheral, and autonomic nervous system are common in systemic lupus erythematosus (SLE); collectively, these symptoms are termed neuropsychiatric SLE (NPSLE). Among a wide variety of neuropsychiatric symptoms, depression is observed in about 24-39% of SLE patients. Several cytokines and chemokines have been identified as biomarkers or therapeutic targets of NPSLE; in particular, the levels of type 1 interferons, TNFs, and IL-6 are elevated in SLE patient's cerebrospinal fluid (CSF), and these factors contribute to the pathology of depression. Here, we show that senescent neural cells accumulate in the hippocampal cornu ammonis 3 (CA3) region in MRL/lpr SLE model mice with depressive behavior. Furthermore, oral administration of fisetin, a senolytic drug, reduced the number of senescent neural cells and reduced depressive behavior in the MRL/lpr mice. In addition, transcription of several senescence and senescence-associated secretory phenotype (SASP) factors in the hippocampal region also decreased after fisetin treatment in the MRL/lpr mice. These results indicate that the accumulation of senescent neural cells in the hippocampus plays a role in NPSLE pathogenesis, and therapies targeting senescent cells may represent a candidate approach to treat NPSLE.

Keywords:  SASP (senescence-associated secretory phenotype); depression; inflammation; senescence; systemic lupus erythematosus

DOI:  https://doi.org/10.3389/fimmu.2021.692321
J Inflamm Res. 2021 ;14 6025-6041

The Immunomodulatory Functions of Butyrate.

Mohamed Tausif Siddiqui, Gail A M Cresci.

  The gastrointestinal (GI) system contains many different types of immune cells, making it a key immune organ system in the human body. In the last decade, our knowledge has substantially expanded regarding our understanding of the gut microbiome and its complex interaction with the gut immune system. Short chain fatty acids (SCFA), and specifically butyrate, play an important role in mediating the effects of the gut microbiome on local and systemic immunity. Gut microbial alterations and depletion of luminal butyrate have been well documented in the literature for a number of systemic and GI inflammatory disorders. Although a substantial knowledge gap exists requiring the need for further investigations to determine cause and effect, there is heightened interest in developing immunomodulatory therapies by means of reprogramming of gut microbiome or by supplementing its beneficial metabolites, such as butyrate. In the current review, we discuss the role of endogenous butyrate in the inflammatory response and maintaining immune homeostasis within the intestine. We also present the experimental models and human studies which explore therapeutic potential of butyrate supplementation in inflammatory conditions associated with butyrate depletion.

Keywords:  adaptive immunity; butyrate; dysbiosis; epithelial barrier; gut microbiome; gut microbiota; immunity; inflammation; inflammatory bowel disease; innate immunity; short chain fatty acids

DOI:  https://doi.org/10.2147/JIR.S300989
J Immunol. 2021 Nov 24. pii: ji2100769. [Epub ahead of print]

Nanoparticle-Induced Airway Eosinophilia Is Independent of ILC2 Signaling but Associated With Sex Differences in Macrophage Phenotype Development.

Jessica L Ray, Pam K Shaw, Britten Postma, Celine A Beamer, Andrij Holian.

The majority of lung diseases occur with a sex bias in terms of prevalence and/or severity. Previous studies demonstrated that, compared with males, female mice develop greater eosinophilic inflammation in the airways after multiwalled carbon nanotube (MWCNT) exposure. However, the mechanism by which this sex bias occurs is unknown. Two immune cells that could account for the sex bias are type II innate lymphoid cells (ILC2s) and alveolar macrophages (AMs). In order to determine which immune cell type was responsible for MWCNT-induced airway eosinophil recruitment and subsequent sex differences in inflammation and disease, male and female C57BL/6 mice were exposed to MWCNTs (2 mg/kg) via oropharyngeal aspiration, and the respiratory immune response was assessed 7 d later. Greater eosinophilia and eotaxin 2 levels were observed in MWCNT-treated females and corresponded with greater changes in airway hyperresponsiveness than those in MWCNT-treated males. In MWCNT-treated females, there was a significant increase in the frequency of ILC2s within the lungs compared with control animals. However, depletion of ILC2s via α-CD90.2 administration did not decrease eosinophil recruitment 24 h and 7 d after MWCNT exposure. AMs isolated from control and MWCNT-treated animals demonstrated that M2a macrophage phenotype gene expression, ex vivo cytokine production, and activation of (p)STAT6 were upregulated to a significantly greater degree in MWCNT-treated females than in males. Our findings suggest that sex differences in AM phenotype development, not ILC2 signaling, are responsible for the observed female bias in eosinophilic inflammation after MWCNT inhalation.

DOI: https://doi.org/10.4049/jimmunol.2100769
Cell Mol Immunol. 2021 Nov 26.

Resident and migratory adipose immune cells control systemic metabolism and thermogenesis.

Kevin Man, Axel Kallies, Ajithkumar Vasanthakumar.

  Glucose is a vital source of energy for all mammals. The balance between glucose uptake, metabolism and storage determines the energy status of an individual, and perturbations in this balance can lead to metabolic diseases. The maintenance of organismal glucose metabolism is a complex process that involves multiple tissues, including adipose tissue, which is an endocrine and energy storage organ that is critical for the regulation of systemic metabolism. Adipose tissue consists of an array of different cell types, including specialized adipocytes and stromal and endothelial cells. In addition, adipose tissue harbors a wide range of immune cells that play vital roles in adipose tissue homeostasis and function. These cells contribute to the regulation of systemic metabolism by modulating the inflammatory tone of adipose tissue, which is directly linked to insulin sensitivity and signaling. Furthermore, these cells affect the control of thermogenesis. While lean adipose tissue is rich in type 2 and anti-inflammatory cytokines such as IL-10, obesity tips the balance in favor of a proinflammatory milieu, leading to the development of insulin resistance and the dysregulation of systemic metabolism. Notably, anti-inflammatory immune cells, including regulatory T cells and innate lymphocytes, protect against insulin resistance and have the characteristics of tissue-resident cells, while proinflammatory immune cells are recruited from the circulation to obese adipose tissue. Here, we review the key findings that have shaped our understanding of how immune cells regulate adipose tissue homeostasis to control organismal metabolism.

Keywords:  adipose tissue; immune cells; metabolism

DOI:  https://doi.org/10.1038/s41423-021-00804-7
Hepatol Commun. 2021 Nov 26.

High-Resolution Exposomics and Metabolomics Reveals Specific Associations in Cholestatic Liver Diseases.

Douglas I Walker, Brian D Juran, Angela C Cheung, Erik M Schlicht, Yongliang Liang, Megan Niedzwiecki, Nicholas F LaRusso, Gregory J Gores, Dean P Jones, Gary W Miller, Konstantinos N Lazaridis.

Progress in development of prognostic and therapeutic options for the rare cholestatic liver diseases, primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), is hampered by limited knowledge of their pathogeneses. In particular, the potential role of hepatotoxic and/or metabolism-altering environmental chemicals in the pathogenesis of these diseases remains relatively unstudied. Moreover, the extent to which metabolic pathways are altered due to ongoing cholestasis and subsequent liver damage or possibly influenced by hepatotoxic chemicals is poorly understood. In this study, we applied a comprehensive exposomics-metabolomics approach to uncover potential pathogenic contributors to PSC and PBC. We used untargeted high-resolution mass spectrometry to characterize a wide range of exogenous chemicals and endogenous metabolites in plasma and tested them for association with disease. Exposome-wide association studies (EWAS) identified environmental chemicals, including pesticides, additives and persistent pollutants, that were associated with PSC and/or PBC, suggesting potential roles for these compounds in disease pathogenesis. Metabolome-wide association studies (MWAS) found disease-associated alterations to amino acid, eicosanoid, lipid, co-factor, nucleotide, mitochondrial and microbial metabolic pathways, many of which were shared between PSC and PBC. Notably, this analysis implicates a potential role of the 5-lipoxygenase pathway in the pathogenesis of these diseases. Finally, EWAS × MWAS network analysis uncovered linkages between environmental agents and disrupted metabolic pathways that provide insight into potential mechanisms for PSC and PBC. Conclusion: This study establishes combined exposomics-metabolomics as a generalizable approach to identify potentially pathogenic environmental agents and enumerate metabolic alterations that may impact PSC and PBC, providing a foundation for diagnostic and therapeutic strategies.

DOI: https://doi.org/10.1002/hep4.1871
J Virol. 2021 Nov 24. JVI0139421

Novel humanized-PBMC mouse model with delayed onset of GVHD for preclinical HIV research.

Leo Holguin, Liliana Echavarria, John C Burnetta.

Humanized mouse models are based on the engraftment of human cells in immunodeficient mouse strains, most notably the NSG strain. Most used models have a major limitation in common, the development of graft-versus-host disease (GVHD). GVHD not only introduces variabilities into the research data but also leads to animal welfare concerns. A new mouse strain, B6.129S-Rag2tm1Fwa CD47tm1Fpl Il2rgtm1Wjl/J which lacks Rag1, IL2rg, and CD47 (triple knockout or TKO), is resistant to GVHD development. We transplanted TKO mice with human peripheral blood mononuclear cells (PBMCs) to establish a new humanized PBMC (hu-PBMC) mouse model. A cohort of these mice was infected with HIV-1 and monitored for plasma HIV viremia and CD4+ T cell depletion. The onset and progression of GVHD were monitored by clinical signs. This study demonstrates that TKO mice transplanted with human PBMCs support engraftment of human immune cells in primary and secondary lymphoid tissues, rectum, and brain. Moreover, the TKO hu-PBMC model supports HIV-1 infection via intraperitoneal, rectal, or vaginal routes, as confirmed by robust plasma HIV viremia and CD4+ T cell depletion. Lastly, TKO mice showed a delayed onset of GVHD clinical signs (∼28 days) and exhibited significant decreases in plasma levels of TNFβ. Based on these results, the TKO hu-PBMC mouse model not only supports humanization and HIV-1 infection but also has a delayed onset of GVHD development, making this model a valuable tool in HIV research. Importance Currently, there is no cure or vaccine for HIV infection, thus continued research is needed to end the HIV pandemic. While many animal models are used in HIV research, none is used more than the humanized mouse model. A major limitation with current humanized mouse models is the development of graft-versus-host disease (GVHD). Here, we show a novel humanized-PBMC mouse model that has a delayed onset GVHD development and supports and models HIV infection comparable to well-established humanized mouse models.

DOI: https://doi.org/10.1128/JVI.01394-21
JHEP Rep. 2022 Jan;4(1): 100387

Bile acids contribute to the development of non-alcoholic steatohepatitis in mice.

Justine Gillard, Laure-Alix Clerbaux, Maxime Nachit, Christine Sempoux, Bart Staels, Laure B Bindels, Anne Tailleux, Isabelle A Leclercq.

   Background & Aims: Through FXR and TGR5 signaling, bile acids (BAs) modulate lipid and glucose metabolism, inflammation and fibrosis. Hence, BAs returning to the liver after enteric secretion, modification and reabsorption may contribute to the pathogenesis of non-alcoholic steatohepatitis (NASH). Herein, we characterized the enterohepatic profile and signaling of BAs in preclinical models of NASH, and explored the consequences of experimental manipulation of BA composition.
Methods: We used high-fat diet (HFD)-fed foz/foz and high-fructose western diet-fed C57BL/6J mice, and compared them to their respective controls. Mice received a diet supplemented with deoxycholic acid (DCA) to modulate BA composition.
Results: Compared to controls, mice with NASH had lower concentrations of BAs in their portal blood and bile, while systemic BA concentrations were not significantly altered. Notably, the concentrations of secondary BAs, and especially of DCA, and the ratio of secondary to primary BAs were strikingly lower in bile and portal blood of mice with NASH. Hence, portal blood was poor in FXR and TGR5 ligands, and conferred poor anti-inflammatory protection in mice with NASH. Enhanced primary BAs synthesis and conversion of secondary to primary BAs in NASH livers contributed to the depletion in secondary BAs. Dietary DCA supplementation in HFD-fed foz/foz mice restored the BA concentrations in portal blood, increased TGR5 and FXR signaling, improved the dysmetabolic status, protected from steatosis and hepatocellular ballooning, and reduced macrophage infiltration.
Conclusions: BA composition in the enterohepatic cycle, but not in systemic circulation, is profoundly altered in preclinical models of NASH, with specific depletion in secondary BAs. Dietary correction of the BA profile protected from NASH, supporting a role for enterohepatic BAs in the pathogenesis of NASH.
Lay summary: This study clearly demonstrates that the alterations of enterohepatic bile acids significantly contribute to the development of non-alcoholic steatohepatitis in relevant preclinical models. Indeed, experimental modulation of bile acid composition restored perturbed FXR and TGR5 signaling and prevented non-alcoholic steatohepatitis and associated metabolic disorders.

Keywords:  ASBT, apical sodium-dependent BA transporter; BA, bile acid; CA, cholic acid; CDCA, chenodeoxycholic acid; CYP27A1, sterol 27-hydroxylase; CYP2A12, bile acid 7α-hydroxylase; CYP7A1, cholesterol 7α-hydroxylase; CYP7B1, oxysterol 7α-hydroxylase; CYP8B1, sterol 12α-hydroxylase; DCA, deoxycholic acid; FABP6, fatty acid binding protein 6; FGF15, fibroblast growth factor 15; FGFR4, fibroblast growth factor receptor 4; FXR; FXR, Farnesoid X receptor; GLP-1, glucagon-like peptide-1; HFD, high-fat diet; LCA, lithocholic acid; LPS, lipopolysaccharide; NAFLD; NAFLD, non-alcoholic fatty liver disease; NAS, NAFLD activity score; NASH; NASH, non-alcoholic steatohepatitis; ND, normal diet; OGTT, oral glucose tolerance test; OST, organic solute transporter; SHP, small heterodimer protein; TGR5; TGR5, Takeda G-protein coupled receptor 5; TLCA, tauro-lithocholic acid; TNFα, tumor necrosis factor α; WDF, western and high-fructose diet; WT, wild-type; metabolic syndrome; αMCA, α-muricholic acid; βMCA, β-muricholic acid; ωMCA, ω-muricholic acid

DOI:  https://doi.org/10.1016/j.jhepr.2021.100387
iScience. 2021 Nov 19. 24(11): 103339

Resolving macrophage polarization through distinct Ca2+ entry channel that maintains intracellular signaling and mitochondrial bioenergetics.

Viviane Nascimento Da Conceicao, Yuyang Sun, Karthik Ramachandran, Arun Chauhan, Amritha Raveendran, Manigandan Venkatesan, Bony DeKumar, Soumya Maity, Neelanjan Vishnu, George A Kotsakis, Paul F Worley, Donald L Gill, Bibhuti B Mishra, Muniswamy Madesh, Brij B Singh.

  Transformation of naive macrophages into classically (M1) or alternatively (M2) activated macrophages regulates the inflammatory response. Here, we identified that distinct Ca2+ entry channels determine the IFNγ-induced M1 or IL-4-induced M2 transition. Naive or M2 macrophages exhibit a robust Ca2+ entry that was dependent on Orai1 channels, whereas the M1 phenotype showed a non-selective TRPC1 current. Blockade of Ca2+ entry suppresses pNF-κB/pJNK/STAT1 or STAT6 signaling events and consequently lowers cytokine production that is essential for M1 or M2 functions. Of importance, LPS stimulation shifted M2 cells from Orai1 toward TRPC1-mediated Ca2+ entry and TRPC1-/- mice exhibited transcriptional changes that suppress pro-inflammatory cytokines. In contrast, Orai1-/- macrophages showed a decrease in anti-inflammatory cytokines and exhibited a suppression of mitochondrial oxygen consumption rate and inhibited mitochondrial shape transition specifically in the M2 cells. Finally, alterations in TRPC1 or Orai1 expression determine macrophage polarization suggesting a distinct role of Ca2+ channels in modulating macrophage transformation.

Keywords:  Immune system; Molecular biology; Molecular network

DOI:  https://doi.org/10.1016/j.isci.2021.103339
J Immunol. 2021 Nov 24. pii: ji2100503. [Epub ahead of print]

Stereotypic Expansion of T Regulatory and Th17 Cells during Infancy Is Disrupted by HIV Exposure and Gut Epithelial Damage.

Sonwabile Dzanibe, Katie Lennard, Agano Kiravu, Melanie S S Seabrook, Berenice Alinde, Susan P Holmes, Catherine A Blish, Heather B Jaspan, Clive M Gray.

Few studies have investigated immune cell ontogeny throughout the neonatal and early pediatric period, when there is often increased vulnerability to infections. In this study, we evaluated the dynamics of two critical T cell populations, T regulatory (Treg) cells and Th17 cells, over the first 36 wk of human life. First, we observed distinct CD4+ T cells phenotypes between cord blood and peripheral blood, collected within 12 h of birth, showing that cord blood is not a surrogate for newborn blood. Second, both Treg and Th17 cells expanded in a synchronous fashion over 36 wk of life. However, comparing infants exposed to HIV in utero, but remaining uninfected, with HIV-unexposed uninfected control infants, there was a lower frequency of peripheral blood Treg cells at birth, resulting in a delayed expansion, and then declining again at 36 wk. Focusing on birth events, we found that Treg cells coexpressing CCR4 and α4β7 inversely correlated with plasma concentrations of CCL17 (the ligand for CCR4) and intestinal fatty acid binding protein, IL-7, and CCL20. This was in contrast with Th17 cells, which showed a positive association with these plasma analytes. Thus, despite the stereotypic expansion of both cell subsets over the first few months of life, there was a disruption in the balance of Th17 to Treg cells at birth likely being a result of gut damage and homing of newborn Treg cells from the blood circulation to the gut.

DOI: https://doi.org/10.4049/jimmunol.2100503
Nat Immunol. 2021 Nov 22.

Mitochondrial aspartate regulates TNF biogenesis and autoimmune tissue inflammation.

Bowen Wu, Tuantuan V Zhao, Ke Jin, Zhaolan Hu, Matthew P Abdel, Ken J Warrington, Jörg J Goronzy, Cornelia M Weyand.

Misdirected immunity gives rise to the autoimmune tissue inflammation of rheumatoid arthritis, in which excess production of the cytokine tumor necrosis factor (TNF) is a central pathogenic event. Mechanisms underlying the breakdown of self-tolerance are unclear, but T cells in the arthritic joint have a distinctive metabolic signature of ATPlo acetyl-CoAhi proinflammatory effector cells. Here we show that a deficiency in the production of mitochondrial aspartate is an important abnormality in these autoimmune T cells. Shortage of mitochondrial aspartate disrupted the regeneration of the metabolic cofactor nicotinamide adenine dinucleotide, causing ADP deribosylation of the endoplasmic reticulum (ER) sensor GRP78/BiP. As a result, ribosome-rich ER membranes expanded, promoting co-translational translocation and enhanced biogenesis of transmembrane TNF. ERrich T cells were the predominant TNF producers in the arthritic joint. Transfer of intact mitochondria into T cells, as well as supplementation of exogenous aspartate, rescued the mitochondria-instructed expansion of ER membranes and suppressed TNF release and rheumatoid tissue inflammation.

DOI: https://doi.org/10.1038/s41590-021-01065-2