DOCSLIB.ORG

Influenza Infection Triggers Disease in a Genetic Model of Experimental

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Influenza Infection Triggers Disease in a Genetic Model of Experimental Influenza infection triggers disease in a genetic model PNAS PLUS of experimental autoimmune encephalomyelitis Stephen Blackmorea, Jessica Hernandeza, Michal Judaa, Emily Ryderb, Gregory G. Freunda,c, Rodney W. Johnsona,b,d, and Andrew J. Steelmana,b,d,1 aDepartment of Animal Sciences, University of Illinois Urbana–Champaign, Urbana, IL 61801; bNeuroscience Program, University of Illinois Urbana–Champaign, Urbana, IL 61801; cDepartment of Pathology, University of Illinois Urbana–Champaign, Urbana, IL 61801; and dDivision of Nutritional Sciences, University of Illinois Urbana–Champaign, Urbana, IL 61801 Edited by Lawrence Steinman, Stanford University School of Medicine, Stanford, CA, and approved June 13, 2017 (received for review December 13, 2016) Multiple sclerosis (MS) is an autoimmune disease of the central affect the progression of many neurological diseases including nervous system. Most MS patients experience periods of symptom Alzheimer’s disease (10, 11), Parkinson’s disease (12), and exacerbation (relapses) followed by periods of partial recovery multiple sclerosis (13–17). (remission). Interestingly, upper-respiratory viral infections increase We are interested in determining how upper-respiratory in- the risk for relapse. Here, we used an autoimmune-prone T-cell fection contributes to the progression of neurological dis- receptor transgenic mouse (2D2) and a mouse-adapted human eases including multiple sclerosis (MS), the most prominent influenza virus to test the hypothesis that upper-respiratory viral autoimmune-mediated demyelinating and neurodegenerating infection can cause glial activation, promote immune cell trafficking disease of the CNS. The majority of MS patients exhibit an os- to the CNS, and trigger disease. Specifically, we inoculated 2D2 mice cillating disease course that is characterized by relatively short with influenza A virus (Puerto Rico/8/34; PR8) and then monitored periods of neurological dysfunction followed by periods of re- them for symptoms of inflammatory demyelination. Clinical and mission, termed relapsing-remitting MS (18). Importantly, both histological experimental autoimmune encephalomyelitis was ob- relapse rate and intervals between relapses are predictors of served in ∼29% of infected 2D2 mice. To further understand how disability outcome and relapses contribute to the development of peripheral infection could contribute to disease onset, we inocu- permanent neurological dysfunction (19). Interestingly, within 5 lated wild-type C57BL/6 mice and measured transcriptomic alter- weeks of contracting an upper-respiratory infection an estimated INFLAMMATION ations occurring in the cerebellum and spinal cord and monitored 27–41% of patients will suffer disease exacerbation (13, 15, 16, IMMUNOLOGY AND immune cell surveillance of the CNS by flow cytometry. Infection 20–22). In addition, some reports suggest that relapses occurring caused temporal alterations in the transcriptome of both the cere- around the time of infection are associated with sustained neu- bellum and spinal cord that was consistent with glial activation and rological deficits, increased relapse severity, and an increased increased T-cell, monocyte, and neutrophil trafficking to the brain at number of gadolinium-enhancing lesions as measured by MRI day 8 post infection. Finally, Cxcl5 expression was up-regulated in (21). Picornaviruses have been identified as triggers of relapse the brains of influenza-infected mice and was elevated in cerebro- (13, 23), but infection with other viruses, including influenza A spinal fluid of MS patients during relapse compared with specimens virus, has also been associated with exacerbated disease (24). acquired during remission. Collectively, these data identify a mech- These data suggest that upper-respiratory infection with viral anism by which peripheral infection may exacerbate MS as well as pathogens can precipitate relapse, but the mechanisms remain other neurological diseases. poorly defined. In the case of MS patients, it is possible that upper-respiratory upper-respiratory viral infection | multiple sclerosis | neuroinflammation | infection-induced glial activation triggers immune surveillance immune cell surveillance | experimental autoimmune encephalomyelitis Significance he bidirectional connectivity between the brain and the im- Tmune system is well-established. It has been repeatedly Peripheral infections exacerbate symptoms of many neuro- demonstrated that systemic inflammation brought on by activa- logical diseases, including the most common autoimmune de- tion of toll-like receptors (TLRs) on cells in the periphery can myelinating disease of the central nervous system (CNS), trigger glial activation in mice and humans (1–3). Furthermore, multiple sclerosis (MS). We demonstrate that influenza viral upper-respiratory infection with influenza A (4, 5) and porcine infection of autoimmune-prone mice triggers clinical and his- reproductive and respiratory syndrome viruses up-regulate tological disease. We further show that influenza infection al- proinflammatory cytokines within the CNS and cause alter- ters the transcriptome of the central nervous system and ations to the microglial sensome (6). Under normal physio- facilitates immune cell trafficking to the brain. Finally, we logical circumstances, activation of glial cells by peripheral identified a specific chemokine that is upregulated in the CNS inflammatory processes likely facilitate functions that are es- during infection that is also increased in the cerebrospinal fluid sential for the maintenance of homeostasis. For example, type I of MS patients during relapse. These observations improve our IFN signaling to brain endothelial cells contributes to the understanding of how peripheral infection may act to exacer- development of sickness behaviors in rodents, which are im- bate neurological diseases such as multiple sclerosis. portant for combating infection (7). Furthermore, systemic Author contributions: A.J.S. designed research; S.B., J.H., M.J., E.R., G.G.F., and A.J.S. inflammation-induced glial activation promotes immune sur- performed research; G.G.F., R.W.J., and A.J.S. contributed new reagents/analytic tools; veillance of the CNS (2, 8). The function of this surveillance is S.B., J.H., M.J., E.R., and A.J.S. analyzed data; and S.B. and A.J.S. wrote the paper. not entirely clear, but may serve to protect against infection of The authors declare no conflict of interest. the CNS parenchyma and under certain circumstances facilitate This article is a PNAS Direct Submission. repair (9). Conversely, aberrant neuroinflammation contributes Data deposition: The sequence reported in this paper has been deposited in the NIH Gene to the pathogenesis of a myriad of neurological diseases and Expression Omnibus database (accession no. GSE96870). T-cell extravasation into the CNS is not always beneficial. In- 1To whom correspondence should be addressed. Email: [email protected]. triguingly, systemic inflammation brought on by pathogenic in- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. fection can exacerbate neuroinflammatory processes and may 1073/pnas.1620415114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1620415114 PNAS Early Edition | 1of10 Downloaded by guest on October 1, 2021 of the CNS that may be detrimental. To model the effects of upper-respiratory infection on relapse and/or disease progres- sion in MS patients, we infected autoimmune-prone T-cell re- ceptor transgenic (2D2) mice with mouse-adapted human influenza A virus. This strategy was chosen because, although + ∼90% of CD4 T-cells in 2D2 mice express a T-cell receptor (TCR) with specificity for myelin oligodendrocyte glycopro- tein (MOG35–55) and neurofilament-m (NF-M18–30), few (4%) develop spontaneous classic experimental autoimmune en- cephalomyelitis (EAE) (25). Additionally, the presence of circu- lating autoreactive cells enabled us to bypass the need to polarize and activate T-cells before injection. Finally, influ- enza A virus can induce glial activation (4, 5) and has been associated with increased relapse risk in MS patients (22, 24, 26). Here, we report that upper-respiratory infection with influenza virus is capable of causing neurological disease in 2D2 mice. Furthermore, we found that viral infection alone caused temporal transcriptomic changes to the cerebellum and spinal cord that were in part mediated by IFN signaling. Finally, we demonstrate that infection caused immune cell surveillance of the CNS. Fig. 1. CNS pathology in saline- and influenza-infected 2D2 mice. (A and B) Transgenic 2D2 mice were inoculated with saline (n = 5) or influenza (n = 8; Results 0.7 HAU). After 28 d post infection, mice were euthanized. Brains and spinal cord sections were stained with H&E to identify inflammation and Luxol Fast Influenza A Infection Causes EAE Onset in 2D2 Mice. Transgenic + Blue and periodic acid Schiff (LFB/PAS) to identify demyelination. Sections 2D2 mice possess an inherent reduction in CD8 T-cells that were scanned by a rater blinded to condition. (A) Spinal cord lesion showing might impede virus-specific immune responses (25). Indeed, inflammation (Top) and demyelination (Bottom) in an influenza-infected following intranasal inoculation with a normally nonlethal dose mouse. (Right) Higher magnification of lesion is denoted by an asterisk. of influenza [1.0 hemagglutinating unit (HAU)], 2D2 mice lost (Scale bar is 50 μm.) (B) Representative cerebellar H&E (Top) and LFB/PAS
Load more

Recommended publications
  • Differentiation and Bone Resorption Role of CX3CL1/Fractalkine In
    Role of CX3CL1/Fractalkine in Osteoclast Differentiation and Bone Resorption Keiichi Koizumi, Yurika Saitoh, Takayuki Minami, Nobuhiro Takeno, Koichi Tsuneyama, Tatsuro Miyahara, This information is current as Takashi Nakayama, Hiroaki Sakurai, Yasuo Takano, Miyuki of September 29, 2021. Nishimura, Toshio Imai, Osamu Yoshie and Ikuo Saiki J Immunol published online 18 November 2009 http://www.jimmunol.org/content/early/2009/11/18/jimmuno l.0803627.citation Downloaded from Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 29, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published November 18, 2009, doi:10.4049/jimmunol.0803627 The Journal of Immunology Role of CX3CL1/Fractalkine in Osteoclast Differentiation and Bone Resorption1 Keiichi Koizumi,2* Yurika Saitoh,* Takayuki Minami,* Nobuhiro Takeno,* Koichi Tsuneyama,†‡ Tatsuro Miyahara,§ Takashi Nakayama,¶ Hiroaki Sakurai,*† Yasuo Takano,‡ Miyuki Nishimura,ʈ Toshio Imai,ʈ Osamu Yoshie,¶ and Ikuo Saiki*† The recruitment of osteoclast precursors toward osteoblasts and subsequent cell-cell interactions are critical for osteoclast dif- ferentiation.
    [Show full text]
  • S41467-017-02610-0.Pdf
    ARTICLE DOI: 10.1038/s41467-017-02610-0 OPEN Angiogenic factor-driven inflammation promotes extravasation of human proangiogenic monocytes to tumours Adama Sidibe 1,4, Patricia Ropraz1, Stéphane Jemelin1, Yalin Emre 1, Marine Poittevin1, Marc Pocard2,3, Paul F. Bradfield1 & Beat A. Imhof1 1234567890():,; Recruitment of circulating monocytes is critical for tumour angiogenesis. However, how human monocyte subpopulations extravasate to tumours is unclear. Here we show mechanisms of extravasation of human CD14dimCD16+ patrolling and CD14+CD16+ inter- mediate proangiogenic monocytes (HPMo), using human tumour xenograft models and live imaging of transmigration. IFNγ promotes an increase of the chemokine CX3CL1 on vessel lumen, imposing continuous crawling to HPMo and making these monocytes insensitive to chemokines required for their extravasation. Expression of the angiogenic factor VEGF and the inflammatory cytokine TNF by tumour cells enables HPMo extravasation by inducing GATA3-mediated repression of CX3CL1 expression. Recruited HPMo boosts angiogenesis by secreting MMP9 leading to release of matrix-bound VEGF-A, which amplifies the entry of more HPMo into tumours. Uncovering the extravasation cascade of HPMo sets the stage for future tumour therapies. 1 Department of Pathology and Immunology, Centre Médical Universitaire (CMU), Medical faculty, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneva, Switzerland. 2 Department of Oncologic and Digestive Surgery, AP-HP, Hospital Lariboisière, 2 rue Ambroise Paré, F-75475 Paris cedex 10, France. 3 Université Paris Diderot, Sorbonne Paris Cité, CART, INSERM U965, 49 boulevard de la Chapelle, F-75475 Paris cedex 10, France. 4Present address: Department of Physiology and Metabolism, Centre Médical Universitaire (CMU), Medical faculty, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneva, Switzerland.
    [Show full text]
  • The Role of Type I Interferon in the Immunobiology of Chikungunya Virus
    The role of type I interferon in the immunobiology of chikungunya virus Jane Amelia Clare Wilson B. App. Sc. (Human Biology), B. App. Sc. (Hons) A thesis submitted for the degree of Doctor of Philosophy at The University of Queensland in 2015 School of Medicine & QIMR Berghofer Medical Research Institute I Abstract Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that can cause explosive outbreaks of a febrile, arthritic/arthralgic disease usually lasting weeks to months, and in rare cases, more than a year. In 2004, the largest ever CHIKV outbreak began in Kenya, spreading to islands of the Indian Ocean, India, South East Asia and major outbreaks have recently occurred in the South Pacific Islands and the Caribbean. The host type I interferon (IFN) response is crucial for effective control of CHIKV infection. Herein, the dynamics, source and responses generated by the type I IFNs following CHIKV infection were investigated. Interferon regulatory factors 3 (IRF3) and IRF7 are key transcription factors for the type I IFN response. While CHIKV infection of wild-type mice is non-lethal, infection of mice deficient in both IRF3 and IRF7 (IRF3/7-/-) resulted in mortality, illustrating that these factors are essential for protection. Using knockout mice for the adaptor molecules upstream of IRF3 and 7, IPS1 was found to be the most important for type I IFN production, with TRIF and MyD88 also contributing to the response. Mortality in IRF3/7-/- mice was also associated with type I IFN suppression of pathological levels of IFNγ and haemorrhagic shock. Heterozygous reporter mice, in which eGFP was expressed under the control of either the IFNβ or the IFNα6 promoter on one chromosome, were employed to try and identify the cellular source of type I IFN production following CHIVK infection.
    [Show full text]
  • CX3CR1 Deficiency Attenuates DNFB-Induced Contact
    International Journal of Molecular Sciences Article CX3CR1 Deficiency Attenuates DNFB-Induced Contact Hypersensitivity through Skewed Polarization towards M2 Phenotype in Macrophages 1, 1, 1,2, 1,3 Sayaka Otobe y, Teruyoshi Hisamoto y, Tomomitsu Miyagaki * , Sohshi Morimura , Hiraku Suga 1, Makoto Sugaya 1,3 and Shinichi Sato 1 1 Department of Dermatology, the University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan; confi[email protected] (S.O.); [email protected] (T.H.); [email protected] (S.M.); [email protected] (H.S.); [email protected] (M.S.); [email protected] (S.S.) 2 Department of Dermatology, St. Marianna University School of Medicine, Kanagawa 216-8511, Japan 3 Department of Dermatology, International University of Health and Welfare, Chiba 286-0124, Japan * Correspondence: [email protected]; Tel.: +81-44-977-8111; Fax: +81-44-977-3540 These authors contributed equally to this work. y Received: 28 September 2020; Accepted: 5 October 2020; Published: 7 October 2020 Abstract: CX3CL1 can function as both an adhesion molecule and a chemokine for CX3CR1+ cells, such as T cells, monocytes, and NK cells. Recent studies have demonstrated that CX3CL1–CX3CR1 interaction is associated with the development of various inflammatory skin diseases. In this study, we examined CX3CR1 involvement in 2,4-dinitrofluorobenzene (DNFB)-induced contact / hypersensitivity using CX3CR1− − mice. Ear swelling and dermal edema were attenuated after / DNFB challenge in CX3CR1− − mice. Expression of TNF-α, IL-6, and M1 macrophage markers / was decreased in the ears of CX3CR1− − mice, whereas expression of M2 macrophage markers including arginase-1 was increased.
    [Show full text]
  • Treatment with an Anti-CX3CL1 Antibody Suppresses M1 Macrophage Infiltration in Interstitial Lung Disease in SKG Mice
    pharmaceuticals Article Treatment with an Anti-CX3CL1 Antibody Suppresses M1 Macrophage Infiltration in Interstitial Lung Disease in SKG Mice Satoshi Mizutani 1 , Junko Nishio 1,2, Kanoh Kondo 1, Kaori Motomura 1, Zento Yamada 1, Shotaro Masuoka 1, Soichi Yamada 1, Sei Muraoka 1 , Naoto Ishii 3, Yoshikazu Kuboi 3, Sho Sendo 4, Tetuo Mikami 5, Toshio Imai 3 and Toshihiro Nanki 1,* 1 Department of Internal Medicine, Division of Rheumatology, Toho University School of Medicine, Ota-ku, Tokyo 143-8541, Japan; [email protected] (S.M.); [email protected] (J.N.); [email protected] (K.K.); [email protected] (K.M.); [email protected] (Z.Y.); [email protected] (S.M.); [email protected] (S.Y.); [email protected] (S.M.) 2 Department of Immunopathology and Immunoregulation, Toho University School of Medicine, Ota-ku, Tokyo 143-8540, Japan 3 KAN Research Institute, Inc., Chuo-ku, Kobe-shi, Hyogo 650-0047, Japan; [email protected] (N.I.); [email protected] (Y.K.); [email protected] (T.I.) 4 Department of Internal Medicine, Division of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe-shi, Hyogo 650-0017, Japan; [email protected] 5 Department of Pathology, Toho University School of Medicine, Ota-ku, Tokyo 143-8540, Japan; Citation: Mizutani, S.; Nishio, J.; [email protected] Kondo, K.; Motomura, K.; Yamada, Z.; * Correspondence: [email protected]; Tel.: +81-3-3762-4151 (ext.
    [Show full text]
  • Tissue-Specific Role of CX3CR1 Expressing Immune Cells and Their Relationships with Human Disease
    Immune Netw. 2018 Feb;18(1):e5 https://doi.org/10.4110/in.2018.18.e5 pISSN 1598-2629·eISSN 2092-6685 Review Article Tissue-specific Role of CX3CR1 Expressing Immune Cells and Their Relationships with Human Disease Myoungsoo Lee1,2, Yongsung Lee1, Jihye Song1, Junhyung Lee1, Sun-Young Chang1,2,* 1Laboratory of Microbiology, College of Pharmacy, Ajou University, Suwon 16499, Korea 2Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University, Suwon 16499, Korea Received: Oct 14, 2017 ABSTRACT Revised: Dec 31, 2017 Accepted: Jan 1, 2018 Chemokine (C-X3-C motif ) ligand 1 (CX3CL1, also known as fractalkine) and its receptor *Correspondence to chemokine (C-X3-C motif ) receptor 1 (CX3CR1) are widely expressed in immune cells and Sun-Young Chang non-immune cells throughout organisms. However, their expression is mostly cell type- Laboratory of Microbiology, College of specific in each tissue. CX3CR1 expression can be found in monocytes, macrophages, Pharmacy, Ajou University, 164 World cup-ro, dendritic cells, T cells, and natural killer (NK) cells. Interaction between CX3CL1 and CX3CR1 Yeongtong-gu, Suwon 16499, Korea. can mediate chemotaxis of immune cells according to concentration gradient of ligands. E-mail: [email protected] CX3CR1 expressing immune cells have a main role in either pro-inflammatory or anti- Copyright © 2018. The Korean Association of inflammatory response depending on environmental condition. In a given tissue such as Immunologists bone marrow, brain, lung, liver, gut, and cancer, CX3CR1 expressing cells can maintain tissue This is an Open Access article distributed homeostasis. Under pathologic conditions, however, CX3CR1 expressing cells can play a under the terms of the Creative Commons Attribution Non-Commercial License (https:// critical role in disease pathogenesis.
    [Show full text]
  • Stimulation of Innate and Adaptive Immunity by Using Filamentous Bacteriophage Fd Targeted to DEC-205
    Hindawi Publishing Corporation Journal of Immunology Research Volume 2015, Article ID 585078, 11 pages http://dx.doi.org/10.1155/2015/585078 Research Article Stimulation of Innate and Adaptive Immunity by Using Filamentous Bacteriophage fd Targeted to DEC-205 Luciana D’Apice,1 Valerio Costa,2 Rossella Sartorius,1 Maria Trovato,1 Marianna Aprile,2 and Piergiuseppe De Berardinis1 1 Institute of Protein Biochemistry (IBP), National Council of Research, 80131 Naples, Italy 2Institute of Genetics and Biophysics “A. Buzzati-Traverso” (IGB), National Council of Research, 80131 Naples, Italy Correspondence should be addressed to Luciana D’Apice; [email protected] Received 26 March 2015; Accepted 27 May 2015 Academic Editor: L. Leite Copyright © 2015 Luciana D’Apice et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The filamentous bacteriophage fd, codisplaying antigenic determinants and a single chain antibody fragment directed against the dendritic cell receptor DEC-205, is a promising vaccine candidate for its safety and its ability to elicit innate and adaptive immune response in absence of adjuvants. By using a system vaccinology approach based on RNA-Sequencing (RNA-Seq) analysis, we describe a relevant gene modulation in dendritic cells pulsed with anti-DEC-205 bacteriophages fd. RNA-Seq data analysis indicates that the bacteriophage fd virions are sensed as a pathogen by dendritic cells; they activate the danger receptors that trigger an innate immune response and thus confer a strong adjuvanticity that is needed to obtain a long-lasting adaptive immune response.
    [Show full text]
  • Type I Interferon Remodels Lysosome Function and Modifies Intestinal Epithelial Defense
    Type I interferon remodels lysosome function and modifies intestinal epithelial defense Hailong Zhanga,b,c, Abdelrahim Zoueda,b,c, Xu Liua,b,c, Brandon Sitb,c, and Matthew K. Waldora,b,c,1 aHoward Hughes Medical Insitute, Boston, MA 02115; bDivision of Infectious Diseases, Brigham and Women’s Hospital, Boston, MA 02115; and cDepartment of Microbiology, Harvard Medical School, Boston, MA 02115 Edited by Jorge E. Galán, Yale University, New Haven, CT, and approved October 14, 2020 (received for review May 29, 2020) Organelle remodeling is critical for cellular homeostasis, but host the full spectrum of IFN-I-mediated changes in cellular function factors that control organelle function during microbial infection is incomplete. Although IFN-Is are known to play critical roles in remain largely uncharacterized. Here, a genome-scale CRISPR/Cas9 antiviral responses, their functions in bacterial infection are less screen in intestinal epithelial cells with the prototypical intracellu- clear, and IFN-I signaling has been reported to be either pro- lar bacterial pathogen Salmonella led us to discover that type I IFN tective or detrimental to the host depending on the specific (IFN-I) remodels lysosomes. Even in the absence of infection, IFN-I bacterial pathogen (19). signaling modified the localization, acidification, protease activity, Here, we carried out a genome-scale CRISPR/Cas9 screen to and proteomic profile of lysosomes. Proteomic and genetic analyses identify the host factors that contribute to Stm’s cytotoxicity to revealed that multiple IFN-I–stimulated genes including IFITM3, SLC15A3, IECs. This screen revealed IFN-I signaling as a key susceptibility and CNP contribute to lysosome acidification.
    [Show full text]
  • Microglial Responses to Peripheral Type 1 Interferon Ernest Aw1,2, Yingying Zhang1 and Michael Carroll1*
    Aw et al. Journal of Neuroinflammation (2020) 17:340 https://doi.org/10.1186/s12974-020-02003-z RESEARCH Open Access Microglial responses to peripheral type 1 interferon Ernest Aw1,2, Yingying Zhang1 and Michael Carroll1* Abstract Background: Interferon α (IFNα) is a cytokine whose production is increased endogenously in response to viral infection and in autoimmune diseases such as systemic lupus erythematosus (SLE). An elevated IFNα signature has been associated with clinically observed neuro-behavioural deficits such as mild cognitive impairment, fatigue, depression and psychosis in these diseases. However, the mechanisms underlying these neuropsychiatric symptoms remain largely unknown, and it is as yet unclear how IFNα signalling might influence central nervous system (CNS) function. Aberrant microglia-mediated synaptic pruning and function has recently been implicated in several neurodegenerative and neuropsychiatric diseases, but whether and how IFNα modulates these functions are not well defined. Methods: Using a model of peripheral IFNα administration, we investigated gene expression changes due to IFNAR signalling in microglia. Bulk RNA sequencing on sorted microglia from wild type and microglia-specific Ifnar1 conditional knockout mice was performed to evaluate IFNα and IFNAR signalling-dependent changes in gene expression. Furthermore, the effects of IFNα on microglia morphology and synapse engulfment were assessed, via immunohistochemistry and flow cytometry. Results: We found that IFNα exposure through the periphery induces a unique gene signature in microglia that includes the expected upregulation of multiple interferon-stimulated genes (ISGs), as well as the complement component C4b. We additionally characterized several IFNα-dependent changes in microglial phenotype, including expression of CD45 and CD68, cellular morphology and presynaptic engulfment, that reveal subtle brain region- specific differences.
    [Show full text]
  • Combined Genetic and Transcriptome Analysis of Patients With
    Systemic lupus erythematosus Ann Rheum Dis: first published as 10.1136/annrheumdis-2018-214379 on 5 June 2019. Downloaded from TRANSLATIONAL SCIENCE Combined genetic and transcriptome analysis of patients with SLE: distinct, targetable signatures for susceptibility and severity Nikolaos I Panousis, 1,2,3 George K Bertsias, 4,5 Halit Ongen,1,2,3 Irini Gergianaki,4,5 Maria G Tektonidou, 6,7 Maria Trachana,8 Luciana Romano-Palumbo,1 Deborah Bielser,1 Cedric Howald,1,2,3 Cristina Pamfil,9 Antonis Fanouriakis, 10 Despoina Kosmara,4,5 Argyro Repa,4 Prodromos Sidiropoulos,4,5 Emmanouil T Dermitzakis,1,2,3,11 Dimitrios T Boumpas5,7,10,11,12 Handling editor Josef S ABSTRact Key messages Smolen Objectives Systemic lupus erythematosus (SLE) diagnosis and treatment remain empirical and the ► Additional material is What is already known about this subject? published online only. To view molecular basis for its heterogeneity elusive. We explored ► Previous DNA microarray gene expression please visit the journal online the genomic basis for disease susceptibility and severity. studies have identified gene signatures (http:// dx. doi. org/ 10. 1136/ Methods mRNA sequencing and genotyping in blood involved in systemic lupus erythematosus (SLE) annrheumdis- 2018- 214379). from 142 patients with SLE and 58 healthy volunteers. such as those linked to granulocytes, pattern Abundances of cell types were assessed by CIBERSORT For numbered affiliations see recognition receptors, type I interferon and and cell-specific effects by interaction terms in linear end of article. plasmablasts. models. Differentially expressed genes (DEGs) were used Correspondence to to train classifiers (linear discriminant analysis) of SLE What does this study add? Professor Emmanouil T versus healthy individuals in 80% of the dataset and A more comprehensive profiling of the ‘genomic Dermitzakis, Department of were validated in the remaining 20% running 1000 ► Genetic Medicine and architecture’ of SLE by combining genetic and iterations.
    [Show full text]
  • Fractalkine/CX3CL1 Via P38 MAPK Enhances the Adhesion Of
    The CC Chemokine MCP-1 Stimulates Surface Expression of CX3CR1 and Enhances the Adhesion of Monocytes to Fractalkine/CX3CL1 via p38 MAPK This information is current as of September 25, 2021. Simone R. Green, Ki Hoon Han, Yiming Chen, Felicidad Almazan, Israel F. Charo, Yury I. Miller and Oswald Quehenberger J Immunol 2006; 176:7412-7420; ; doi: 10.4049/jimmunol.176.12.7412 Downloaded from http://www.jimmunol.org/content/176/12/7412 References This article cites 52 articles, 29 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/176/12/7412.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 25, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology The CC Chemokine MCP-1 Stimulates Surface Expression of CX3CR1 and Enhances the Adhesion of Monocytes to Fractalkine/CX3CL1 via p38 MAPK1 Simone R.
    [Show full text]
  • Chemokines and Their Receptors in Rheumatoid Arthritis
    ARTHRITIS & RHEUMATISM Vol. 52, No. 3, March 2005, pp 710–721 DOI 10.1002/art.20932 © 2005, American College of Rheumatology REVIEW Chemokines and Their Receptors in Rheumatoid Arthritis Future Targets? Alisa E. Koch Introduction tem was introduced in 2000, in which chemokines are considered as chemokine ligands, and each chemokine Rheumatoid arthritis (RA) is a chronic inflam- has been assigned a designation of CXCL, CCL, XCL, matory disease leading to joint destruction (1). In RA, or CX3CL1 (Figure 1) (10–12). In this report, both the migration of leukocytes into the synovial tissue (ST) former and new nomenclature are noted. occurs. These leukocytes and other cells in the ST, particularly RA ST fibroblasts, produce mediators of CXC chemokines have 2 conserved cysteines inflammation, including chemokines (1). Chemokines, separated by 1 unconserved amino acid (9,13) (Figure currently numbering more than 50, are chemotactic 1). CXC chemokines classically were thought to be cytokines that are important in recruitment of leuko- involved in the chemotaxis of neutrophils. Many chemo- cytes and angiogenesis. They exert chemotactic activity kines may have arisen from reduplication of ancestral toward a variety of cell types (2–7). Some chemokines, genes (13). Hence, CXC chemokines that act on neutro- particularly CXC chemokines containing the ELR motif, phils are clustered on chromosome 4q12–13 (13). How- are angiogenic. The last few years have seen a rapid ever, some genes of more newly discovered CXC che- development of studies aimed at targeting proinflamma- mokines that recruit lymphocytes tend to be located tory chemokines or their receptors in RA and animal away from the major clusters (13).
    [Show full text]