%0 Journal Article
%~ PubMed
%A Hofer, Markus J
%A Li, Wen
%A Manders, Peter
%A Terry, Rachael
%A Lim, Sue Ling
%A King, Nicholas J C
%A Campbell, Iain L
%T Mice deficient in STAT1 but not STAT2 or IRF9 develop a lethal CD4+ T-cell-mediated disease following infection with lymphocytic choriomeningitis virus.
%B Journal of Virology
%D 2012
%C United States
%I American Society for Microbiology
%V 86
%N 12
%P 6932-6946
%@ 1098-5514
%X Interferon (IFN) signaling is crucial for antiviral immunity. While Type I IFN signaling is mediated by STAT1, STAT2 and IRF9, type II IFN signaling requires only STAT1. Here, we studied the role of these signaling factors in the host response to systemic infection with Lymphocytic choriomeningitis virus (LCMV). In wild type (WT) mice and mice lacking either STAT2 or IRF9, LCMV infection was non-lethal and the virus was either cleared (WT) or established persistence (STAT2 KO and IRF9 KO). However, in the case of STAT1 KO mice, LCMV infection was lethal and accompanied by severe multi-organ immune pathology, elevated expression of various cytokine genes in tissues, and cytokines in the serum. This lethal phenotype was unaltered by the co-absence of the IFN-? receptor and hence was not dependent on IFN-?. Equally, this disease was not due to a combined defect in type I and type II IFN signaling as IRF9 mice lacking the IFN-? receptor survived infection with LCMV. Clearance of LCMV is mediated normally by CD8(+) T-cells. However, the depletion of these cells in LCMV-infected STAT1 KO mice delayed, but did not prevent, lethality. By contrast, depletion of CD4(+) T-cells prevented lethality in LCMV-infected STAT1 KO mice and was associated with a reduction in tissue immune pathology. These studies highlight a fundamental difference in the role of STAT1 versus STAT2 and IRF9. While all three factors limit viral replication and spread, only STAT1 has the unique function to prevent the emergence of a lethal antiviral CD4(+) T-cell response.
%Z FOR Codes: 110704 110804 60506


%0 Journal Article
%~ PubMed
%A Getts, Daniel R
%A Terry, Rachael L
%A Getts, Meghann Teague
%A Müller, Marcus
%A Rana, Sabita
%A Deffrasnes, Celine
%A Ashhurst, Thomas Myles
%A Radford, Jane
%A Hofer, Markus
%A Thomas, Shane
%A Campbell, Iain L
%A King, Nicholas Jc
%T Targeted blockade in lethal West Nile virus encephalitis indicates a crucial role for very late antigen (VLA)-4-dependent recruitment of nitric oxide-producing macrophages.
%B Journal of Neuroinflammation
%D 2012
%C United Kingdom
%I BioMed Central Ltd.
%V 9
%N 1
%P 246
%@ 1742-2094
%X 
%Z FOR Codes: 110707 60506 110904


%0 Journal Article
%~ PubMed
%A Ip, Jacque Pk
%A Noçon, Aline L
%A Hofer, Markus J
%A Lim, Sue Ling
%A Müller, Marcus
%A Campbell, Iain L
%T Lipocalin 2 in the central nervous system host response to systemic lipopolysaccharide administration.
%B Journal of Neuroinflammation
%D 2011
%C United Kingdom
%I BioMed Central Ltd.
%V 8
%N 
%P 124
%@ 1742-2094
%X ABSTRACT:
%Z FOR Codes: 110799 60105


%0 Journal Article
%~ PubMed
%A Krauthausen, Marius
%A Ellis, Sally L
%A Zimmermann, Julian
%A Sarris, Maria
%A Wakefield, Denis
%A Heneka, Michael T
%A Campbell, Iain L
%A Müller, Marcus
%T Opposing roles for CXCR3 signaling in central nervous system versus ocular inflammation mediated by the astrocyte-targeted production of IL-12.
%B The American Journal of Pathology
%D 2011
%C United States
%I Elsevier Inc.
%V 179
%N 5
%P 2346-2359
%@ 0002-9440
%X CXCR3 and its ligands are important for the trafficking of activated CD4(+) T(H)1 T cells, CD8(+) T cells, and natural killer cells during inflammation. Recent functional studies demonstrate a more diverse role of CXCR3 in inflammatory diseases of the central nervous system (CNS). We examined the impact of CXCR3 on a less complex interferon-?-dependent, type 1 cell-mediated immune response in the CNS, induced in mice by the transgenic production of glial fibrillary acidic protein IL-12 (GF-IL12) by astrocytes and retinal Müller cells. GF-IL12 mice develop ataxia because of severe cerebellar inflammation but have little overt ocular disease. Surprisingly, CXCR3-deficient GF-IL12 mice (GF-IL12/CXCR3KO) have drastically reduced ataxia but developed cataracts, severe ocular inflammation, and eye atrophy. Most GF-IL12/CXCR3KO mice had minimal cerebellar inflammation but severe retinal disorganization, loss of photoreceptors, and lens destruction in the eye. The number of CD3(+), CD11b(+), and natural killer 1.1(+) cells were reduced in the CNS but highly increased in the eyes of GF-IL12/CXCR3KO compared with GF-IL12 mice. High levels of interferon-?, IL-1, tumor necrosis factor ?, CXCL9, CXCL10, and CCL5 were found in GF-IL12 cerebelli and GF-IL12/CXCR3KO eyes. Our findings demonstrate key but paradoxical functions for CXCR3 in IL-12-induced immune disease in the CNS, promoting inflammation in the brain yet restricting it in the eye. We conclude that the function of CXCR3 in cellular immune disease is driven by a common trigger and is controlled by tissue-specific factors.
%Z FOR Codes: 110703 110904


%0 Journal Article
%~ PubMed
%A Thompson, Claire L
%A Hofer, Markus J
%A Campbell, Iain L
%A Holmes, Andrew J
%T Community dynamics in the mouse gut microbiota: a possible role for IRF9-regulated genes in community homeostasis.
%B PLoS One
%D 2010
%C United States
%I Public Library of Science
%V 5
%N 4
%P e10335
%@ 1932-6203
%X BACKGROUND: Gut microbial communities of mammals are thought to show stable differences between individuals. This means that the properties imparted by the gut microbiota become a unique and constant characteristic of the host. Manipulation of the microbiota has been proposed as a useful tool in health care, but a greater understanding of mechanisms which lead to community stability is required. Here we have examined the impact of host immunoregulatory phenotype on community dynamics. METHODS AND FINDINGS: Denaturing gradient gel electrophoresis was used to analyse the faecal bacterial community of BALB/c and C57BL/6 mice and C57BL/6 mice deficient for either type I interferon (IFN) signalling (IRF9 KO mice) or type I and type II IFN signalling (STAT1 KO mice). Temporal variation was found in all mouse strains. A measure of the ability for a community structure characteristic of the host to be maintained over time, the individuality index, varied between mouse strains and available data from pigs and human models. IRF9 KO mice had significantly higher temporal variation, and lower individuality, than other mouse strains. Examination of the intestinal mucosa of the IRF9 KO mice revealed an increased presence of T-cells and neutrophils in the absence of inflammation. SIGNIFICANCE: The high temporal variation observed in the gut microbiota of inbred laboratory mice has implications for their use as experimental models for the human gut microbiota. The distinct IRF9 and STAT1 phenotypes suggest a role for IRF9 in immune regulation within the gut mucosa and that further study of interferon responsive genes is necessary to understand host-gut microbe relationships.
%Z FOR Codes: 60504 110799


%0 Journal Article
%~ PubMed
%A Ellis, Sally L
%A Gysbers, Vanessa
%A Manders, Peter M
%A Li, Wen
%A Hofer, Markus J
%A Müller, Marcus
%A Campbell, Iain L
%T The Cell-Specific Induction of CXC Chemokine Ligand 9 Mediated by IFN-{gamma} in Microglia of the Central Nervous System Is Determined by the Myeloid Transcription Factor PU.1.
%B Journal of immunology (Baltimore, Md. : 1950)
%D 2010
%C United States
%I American Association of Immunologists
%V 185
%N 3
%P 1864-77
%@ 1550-6606
%X The IFN-gamma-inducible chemokines CXCL9 and CXCL10 are implicated in the pathogenesis of T cell-mediated immunity in the CNS. However, in various CNS immune pathologies the cellular localization of these chemokines differs, with CXCL9 produced by macrophage/microglia whereas CXCL10 is produced by both macrophage/microglia and astrocytes. In this study, we determined the mechanism for the microglial cell-restricted expression of the Cxcl9 gene induced by IFN-gamma. In cultured glial cells, the induction of the CXCL9 (in microglia) and CXCL10 (in microglia and astrocytes) mRNAs by IFN-gamma was not inhibited by cycloheximide. Of various transcription factors involved with IFN-gamma-mediated gene regulation, PU.1 was identified as a constitutively expressed NF in microglia but not in astrocytes. STAT1 and PU.1 bound constitutively to the Cxcl9 gene promoter in microglia, and this increased significantly following IFN-gamma treatment with IFN regulatory factor-8 identified as an additional late binding factor. However, in astrocytes, STAT1 alone bound to the Cxcl9 gene promoter. STAT1 was critical for IFN-gamma induction of both the Cxcl9 and Cxcl10 genes in microglia and in microglia and astrocytes, respectively. The small interfering RNA-mediated knockdown of PU.1 in microglia markedly impaired IFN-gamma-induced CXCL9 but not STAT1 or IFN regulatory factor-8. Cells of the D1A astrocyte line showed partial reprogramming to a myeloid-like phenotype posttransduction with PU.1 and, in addition to the expression of CD11b, acquired the ability to produce CXCL9 in response to IFN-gamma. Thus, PU.1 not only is crucial for the induction of CXCL9 by IFN-gamma in microglia but also is a key determinant factor for the cell-specific expression of this chemokine by these myeloid cells.
%Z FOR Codes: 110799 110904


%0 Journal Article
%~ PubMed
%A Müller, Marcus
%A Carter, Sally
%A Hofer, Markus J
%A Campbell, Iain L
%T The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neuroimmunity - a tale of conflict and conundrum.
%B Neuropathology and applied neurobiology
%D 2010
%C United Kingdom
%I Wiley-Blackwell Publishing Ltd.
%V 36
%N 5
%P 368-87
%@ 1365-2990
%X The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neuroimmunity - a tale of conflict and conundrum The chemokines CXCL9, CXCL10 and CXCL11 (also known as monokine induced by interferon-gamma, interferon-inducible protein-10 and interferon-inducible T cell alpha-chemoattractant, respectively) are structurally and functionally related molecules within the non-ELR CXC chemokine subgroup. These chemokines are generally not detectable in most non-lymphoid tissues under physiological conditions but are strongly induced by cytokines, particularly interferon-gamma, during infection, injury or immunoinflammatory responses. CXCL9, CXCL10 and CXCL11 each bind to a common primary receptor, CXCR3, and possibly to additional receptors. They are best known for their role in leucocyte trafficking, principally acting on activated CD4+ Th1 cells, CD8+ T cells and NK cells. An abundance of data demonstrates that CXCL9, CXCL10 and CXCL11 are produced in many diverse pathologic conditions of the central nervous system. More recent attention has focussed on the function of these chemokines in the central nervous system inflammation. The results of these studies have proven to be sometimes surprising and other times contradictory. Here we discuss the likely more subtle and perhaps divergent roles for these chemokines in the pathogenesis of neuroinflammatory diseases.
%Z FOR Codes: 110799


%0 Journal Article
%~ PubMed
%A Hofer, Markus J
%A Li, Wen
%A Lim, Sue Ling
%A Campbell, Iain L
%T The type I interferon-alpha mediates a more severe neurological disease in the absence of the canonical signaling molecule interferon regulatory factor 9.
%B The Journal of neuroscience : the official journal of the Society for Neuroscience
%D 2010
%C United States
%I Society for Neuroscience
%V 30
%N 3
%P 1149-1157
%@ 1529-2401
%X Type I interferons (IFN) are crucial in host defense but also are implicated as causative factors for neurological disease. Interferon regulatory factor (IRF9) is involved in type I IFN-regulated gene expression where it associates with STAT1:STAT2 heterodimers to form the transcriptional complex ISGF3. The role of IRF9 in cellular responses to type I IFN is poorly defined in vivo and hence was examined here. While transgenic mice (termed GIFN) with chronic production of low levels of IFN-alpha in the CNS were relatively unaffected, the same animals lacking IRF9 [GIFNxIRF9 knock-out (KO)] had cataracts, became moribund, and died prematurely. The brain of GIFNxIRF9 KO mice showed calcification with pronounced inflammation and neurodegeneration whereas inflammation and retinal degeneration affected the eyes. In addition, IFN-gamma-like gene expression in the CNS in association with IFN-gamma mRNA and increased phosphotyrosine-STAT1 suggested a role for IFN-gamma. However, GIFNxIRF9 KO mice deficient for IFN-gamma signaling developed an even more severe and accelerated disease, indicating that IFN-gamma was protective. In IRF9-deficient cultured mixed glial cells, IFN-alpha induced prolonged activation of STAT1 and STAT2 and induced the expression of IFN-gamma-like genes. We conclude that (1) type I IFN signaling and cellular responses can occur in vivo in the absence of IRF9, (2) IRF9 protects against the pathophysiological actions of type I IFN in the CNS, and (3) STAT1 and possibly STAT2 participate in alternative IRF9-independent signaling pathways activated by IFN-alpha in glial cells resulting in enhanced IFN-gamma-like responses.
%Z FOR Codes: 110904 110799 60111


%0 Journal Article
%~ PubMed
%A Campbell, Iain L
%A Hofer, Markus J
%A Pagenstecher, Axel
%T Transgenic models for cytokine-induced neurological disease.
%B Biochimica et biophysica acta
%D 2010
%C Netherlands
%I Elsevier BV
%V 1802
%N 10
%P 903-17
%@ 0006-3002
%X Considerable evidence supports the idea that cytokines are important mediators of pathophysiologic processes within the central nervous system (CNS). Numerous studies have documented the increased production of various cytokines in the human CNS in a variety of neurological and neuropsychiatric disorders. Deciphering cytokine actions in the intact CNS has important implications for our understanding of the pathogenesis and treatment of these disorders. One approach to address this problem that has been used widely employs transgenic mice with CNS-targeted production of different cytokines. Transgenic production of cytokines in the CNS of mice allows not only for the investigation of complex cellular responses at a localized level in the intact brain but also more closely recapitulates the expression of these mediators as found in disease states. As discussed in this review, the findings show that these transgenic animals exhibit wide-ranging structural and functional deficits that are linked to the development of distinct neuroinflammatory responses which are relatively specific for each cytokine. These cytokine-induced alterations often recapitulate those found in various human neurological disorders not only underscoring the relevance of these models but also reinforcing the clinicopathogenetic significance of cytokines in diseases of the CNS.
%Z FOR Codes: 110703 110904


%0 Journal Article
%~ PubMed
%A Quintana, Albert
%A Müller, Marcus
%A Frausto, Ricardo F
%A Ramos, Raquel
%A Getts, Daniel R
%A Sanz, Elisenda
%A Hofer, Markus J
%A Krauthausen, Marius
%A King, Nicholas J C
%A Hidalgo, Juan
%A Campbell, Iain L
%T Site-specific production of IL-6 in the central nervous system retargets and enhances the inflammatory response in experimental autoimmune encephalomyelitis.
%B Journal of Immunology
%D 2009
%C United States
%I American Association of Immunologists
%V 183
%N 3
%P 2079-2088
%@ 0022-1767
%X IL-6 is crucial for the induction of many murine models of autoimmunity including experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. To establish the role of site-specific production of IL-6 in autoimmunity, we examined myelin oligodendrocyte glycoprotein immunization-induced EAE in transgenic mice (GFAP-IL6) with IL-6 production restricted to the cerebellum. Myelin oligodendrocyte glycoprotein-immunized (Mi-) GFAP-IL6 mice developed severe ataxia but no physical signs of spinal cord involvement, which was in sharp contrast to Mi-wild type (WT) animals that developed classical EAE with ascending paralysis. Immune pathology and demyelination were nearly absent from the spinal cord, but significantly increased in the cerebellum of Mi-GFAP-IL6 mice. Tissue damage in the cerebellum in the Mi-GFAP-IL6 mice was accompanied by increased total numbers of infiltrating leukocytes and increased proportions of both neutrophils and B-cells. With the exception of IL-17 mRNA, which was elevated in both control immunized and Mi-GFAP-IL6 cerebellum, the level of other cytokine and chemokine mRNAs were comparable with Mi-WT cerebellum whereas significantly higher levels of IFN-gamma and TNF-alpha mRNA were found in Mi-WT spinal cord. Thus, site-specific production of IL-6 in the cerebellum redirects trafficking away from the normally preferred antigenic site the spinal cord and acts as a leukocyte "sink" that markedly enhances the inflammatory cell accumulation and disease. The mechanisms underlying this process likely include the induction of specific chemokines, activation of microglia, and activation and loss of integrity of the blood-brain barrier present in the cerebellum of the GFAP-IL6 mice before the induction of EAE.
%Z FOR Codes: 110703


%0 Journal Article
%~ PubMed
%A Feuer, Ralph
%A Ruller, Chelsea M
%A An, Naili
%A Tabor-Godwin, Jenna M
%A Rhoades, Ross E
%A Maciejewski, Sonia
%A Pagarigan, Robb R
%A Cornell, Christopher T
%A Crocker, Stephen J
%A Kiosses, William B
%A Pham-Mitchell, Ngan
%A Campbell, Iain L
%A Whitton, J Lindsay
%T Viral persistence and chronic immunopathology in the adult CNS following coxsackievirus infection during the neonatal period.
%B Journal of virology
%D 2009
%C US
%I American Society for Microbiology
%V 83
%N 18
%P 9356-69
%@ 0022-538X
%X Coxsackieviruses are significant human pathogens, and the neonatal central nervous system (CNS) is a major target for infection. Despite the extreme susceptibility of newborn infants to coxsackievirus infection and viral tropism for the CNS, few studies have been aimed at determining the long-term consequences of infection on the developing CNS. We previously described a neonatal mouse model of coxsackievirus B3 (CVB3) infection and determined that proliferating stem cells in the CNS were preferentially targeted. Here, we describe later stages of infection, the ensuing inflammatory response, and subsequent lesions which remain in the adult CNS of surviving animals. High levels of type I interferons and chemokines (in particular MCP-5, IP10, and RANTES) were upregulated following infection and remained at high levels up to day 10 postinfection (p.i). Chronic inflammation and lesions were observed in the hippocampus and cortex of surviving mice for up to 9 months p.i. CVB3 RNA was detected in the CNS up to 3 months p.i at high abundance ( approximately 10(6) genomes/mouse brain), and viral genomic material remained detectable in culture after two rounds of in vitro passage. These data suggest that CVB3 may persist in the CNS as a low-level, noncytolytic infection, causing ongoing inflammatory lesions. Thus, the effects of a relatively common infection during the neonatal period may be long lasting, and the prognosis for newborn infants recovering from acute infection should be reexplored.
%Z FOR Codes: 110799 110904


%0 Journal Article
%~ PubMed
%A Miu, Jenny
%A Mitchell, Andrew J
%A Müller, Marcus
%A Carter, Sally L
%A Manders, Peter M
%A McQuillan, James A
%A Saunders, Bernadette M
%A Ball, Helen J
%A Lu, Bao
%A Campbell, Iain L
%A Hunt, Nicholas H
%T Chemokine gene expression during fatal murine cerebral malaria and protection due to CXCR3 deficiency.
%B Journal of immunology
%D 2008
%C United States
%I American Association of Immunologists
%V 180
%N 2
%P 1217-30
%@ 0022-1767
%X Cerebral malaria (CM) can be a fatal manifestation of Plasmodium falciparum infection. Using murine models of malaria, we found much greater up-regulation of a number of chemokine mRNAs, including those for CXCR3 and its ligands, in the brain during fatal murine CM (FMCM) than in a model of non-CM. Expression of CXCL9 and CXCL10 RNA was localized predominantly to the cerebral microvessels and in adjacent glial cells, while expression of CCL5 was restricted mainly to infiltrating lymphocytes. The majority of mice deficient in CXCR3 were found to be protected from FMCM, and this protection was associated with a reduction in the number of CD8+ T cells in brain vessels as well as reduced expression of perforin and FasL mRNA. Adoptive transfer of CD8+ cells from C57BL/6 mice with FMCM abrogated this protection in CXCR3-/- mice. Moreover, there were decreased mRNA levels for the proinflammatory cytokines IFN-gamma and lymphotoxin-alpha in the brains of mice protected from FMCM. These data suggest a role for CXCR3 in the pathogenesis of FMCM through the recruitment and activation of pathogenic CD8+ T cells.
%Z FOR Codes: 110704 110803


%0 Journal Article
%~ PubMed
%A Quintana, Albert
%A Molinero, Amalia
%A Borup, Rehannah
%A Nielsen, Finn Cilius
%A Campbell, Iain L
%A Penkowa, Milena
%A Hidalgo, Juan
%T Effect of astrocyte-targeted production of IL-6 on traumatic brain injury and its impact on the cortical transcriptome.
%B Developmental neurobiology
%D 2008
%C United States
%I John Wiley & Sons, Inc.
%V 68
%N 2
%P 195-208
%@ 1932-8451
%X Interleukin-6 (IL-6) is one of the key players in the response of the brain cortex to injury. We have described previously that astrocyte-driven production of IL-6 (GFAP-IL6) in transgenic mice, although causing spontaneous neuroinflammation and long term damage, is beneficial after an acute (freeze) injury in the cortex, increasing healing and decreasing oxidative stress and apoptosis. To determine the transcriptional basis for these responses here we analyzed the global gene expression profile of the cortex, at 0 (unlesioned), 1 or 4 days post lesion (dpl), in both GFAP-IL6 mice and their control littermates. GFAP-IL6 mice showed an increase in genes associated with the inflammatory response both at 1 dpl (Iftm1, Endod1) and 4 dpl (Gfap, C4b), decreased expression of proapoptotic genes (i.e. Gadd45b, Clic4, p21) as well as reduced expression of genes involved in the control of oxidative stress (Atf4). Furthermore, the presence of IL-6 altered the expression of genes involved in hemostasis (Vwf), cell migration and proliferation (Cap2), and synaptic activity (Vamp2). All these changes in gene expression could underlie the phenotype of the GFAP-IL6 mice after injury, but many other possible factors were also identified in this study, highlighting the utility of this approach for deciphering new pathways orchestrated by IL-6.
%Z FOR Codes: 110906 110899


%0 Journal Article
%~ PubMed
%A Getts, Daniel R
%A Terry, Rachael L
%A Getts, Meghann Teague
%A Müller, Marcus
%A Rana, Sabita
%A Shrestha, Bimmi
%A Radford, Jane
%A Van Rooijen, Nico
%A Campbell, Iain L
%A King, Nicholas J C
%T Ly6c+ "inflammatory monocytes" are microglial precursors recruited in a pathogenic manner in West Nile virus encephalitis.
%B The Journal of experimental medicine
%D 2008
%C United States
%I Rockefeller University Press
%V 205
%N 0
%P 2319-37
%@ 1540-9538
%X In a lethal West Nile virus (WNV) model, central nervous system infection triggered a threefold increase in CD45(int)/CD11b(+)/CD11c(-) microglia at days 6-7 postinfection (p.i.). Few microglia were proliferating, suggesting that the increased numbers were derived from a migratory precursor cell. Depletion of "circulating" (Gr1(-)(Ly6C(lo))CX3CR1(+)) and "inflammatory" (Gr1(hi)/Ly6C(hi)/CCR2(+)) classical monocytes during infection abrogated the increase in microglia. C57BL/6 chimeras reconstituted with cFMS-enhanced green fluorescent protein (EGFP) bone marrow (BM) showed large numbers of peripherally derived (GFP(+)) microglia expressing GR1(+)(Ly6C(+)) at day 7 p.i., suggesting that the inflammatory monocyte is a microglial precursor. This was confirmed by adoptive transfer of labeled BM (Ly6C(hi)/CD115(+)) or circulating inflammatory monocytes that trafficked to the WNV-infected brain and expressed a microglial phenotype. CCL2 is a chemokine that is highly expressed during WNV infection and important in inflammatory monocyte trafficking. Neutralization of CCL2 not only reduced the number of GFP(+) microglia in the brain during WNV infection but prolonged the life of infected animals. Therefore, CCL2-dependent inflammatory monocyte migration is critical for increases in microglia during WNV infection and may also play a pathogenic role during WNV encephalitis.
%Z FOR Codes: 110799


%0 Journal Article
%~ PubMed
%A Sanz, Elisenda
%A Hofer, Markus J
%A Unzeta, Mercedes
%A Campbell, Iain L
%T Minimal role for STAT1 in interleukin-6 signaling and actions in the murine brain.
%B Glia
%D 2008
%C United States
%I John Wiley & Sons, Inc.
%V 56
%N 2
%P 190-199
%@ 0894-1491
%X Interleukin (IL)-6 is a pleiotropic cytokine whose production by astrocytes in the CNS of transgenic mice (termed GF-IL6) causes neuroinflammation and neurodegeneration. The binding of IL-6 to its receptor (IL6R) triggers gp130-mediated activation of STAT1 and STAT3 as well as SHP2 phosphatase and ERK1/2. We determined the relative contribution of STAT1 to IL-6 signaling and actions in vivo in the brain of GF-IL6 mice. GF-IL6 mice that were null for STAT1 (termed GF-IL6STAT1 KO) were viable, bred normally and physically indistinguishable from GF-IL6 controls. The level of phosphotyrosine (p-Y) STAT1 was increased significantly in GF-IL6 mice but not detectable in GF-IL6STAT1 KO animals. Phospho-STAT3 and phospho-ERK1/2 were increased markedly in GF-IL6 mice and were not altered by the absence of STAT1. Both the density and distribution of phospho-STAT3-positive cells (mainly astrocytes, microglia and endothelial cells) was similar in GF-IL6 and GF-IL6STAT1 KO mice. Despite a minor decrease in IL-1 and TNF mRNA, the overall inflammatory phenotype of GF-IL6 mice was not altered significantly by the absence of STAT1. IFN-regulated genes activated by STAT1 homodimers via the GAS element (e.g. CXCL9) showed a small increase in GF-IL6 but not GF-IL6STAT1 KO animals. When compared with transgenic mice with astrocyte-targeted production of the type I IFN, IFN-alpha, the increased levels of p-Y-STAT1 and IFN-regulated gene expression were considerably lower in GF-IL6 mice. In conclusion, although IL-6 can activate STAT1 this plays minimal, if any, role in IL-6 signaling and actions in the CNS.
%Z FOR Codes: 110906 110899


%0 Journal Article
%~ PubMed
%A Wang, J
%A Campbell, I L
%A Zhang, H
%T Systemic interferon-alpha regulates interferon-stimulated genes in the central nervous system.
%B Molecular psychiatry
%D 2008
%C United Kingdom
%I Nature Publishing Group
%V 13
%N 3
%P 293-301
%@ 1476-5578
%X The prime anti-viral cytokine interferon-alpha (IFN-alpha) has been implicated in several central nervous system (CNS) disorders in addition to its beneficial effects. Systemic IFN-alpha treatment causes severe neuropsychiatric complications in humans, including depression, anxiety and cognitive impairments. While numerous neuromodulatory effects by IFN-alpha have been described, it remains unresolved whether or not systemic IFN-alpha acts directly on the brain to execute its CNS actions. In the present study, we have analyzed the genes directly regulated in post-IFN-alpha receptor signaling and found that intraperitoneal administration of mouse IFN-alpha, but not human IFN-alpha, activated expression of several prototypic IFN-stimulated genes (ISGs), in particular signal transducers and activators of transcription (STAT1), IFN-induced 15 kDa protein (ISG15), ubiquitin-specific proteinase 18 (USP18) and guanylate-binding protein 3 (GBP3) in the brain. A similar temporal profile for the regulated expression of these IFN-alpha-activated ISG genes was observed in the brain compared with the peripheral organs. Dual labeling in situ hybridization combined with immunocytochemical staining demonstrated a wide distribution of the key IFN-regulated gene STAT1 transcripts in the different parenchyma cells of the brain, particularly neurons. The overall response to IFN-alpha challenge was abolished in STAT1 knockout mice. Together, our results indicate a direct, STAT1-dependent action of systemic IFN-alpha in the CNS, which may provide the basis for a mechanism in humans for neurological/neuropsychiatric illnesses associated with IFN-alpha therapy.
%Z FOR Codes: 110903 1108


%0 Journal Article
%~ PubMed
%A Hofer, Markus J
%A Carter, Sally L
%A Müller, Marcus
%A Campbell, Iain L
%T Unaltered Neurological Disease and Mortality in CXCR3-Deficient Mice Infected Intracranially with Lymphocytic Choriomeningitis Virus-Armstrong.
%B Viral Immunology
%D 2008
%C United States
%I Mary Ann Liebert
%V 21
%N 4
%P 425-433
%@ 1557-8976
%X Intracranial infection of mice with lymphocytic choriomeningitis virus (LCMV) results in a lethal neurological disease termed lymphocytic choriomeningitis (LCM) that is mediated by antiviral CD8(+) T cells. Previous studies have implicated the chemokine receptor CXCR3 and its ligand CXCL10 in CD8(+) T cell trafficking in the brain and in the lethal disease following intracranial infection of mice with the LCMV-Traub strain. Here we investigated the role of CXCR3 in LCM following intracranial infection of mice with the LCMV-Armstrong strain. Significant induction of both CXCL9 and CXCL10 RNA and protein was seen in the central nervous system (CNS) in LCM. Cellular localization of the CXCL9 and CXCL10 RNA transcripts was identified predominantly in infiltrating mononuclear cells, as well as in subpial and paraventricular microglia (CXCL9) and astrocytes (CXCL10). Despite a primary role of interferon (IFN)-gamma in inducing the expression of the CXCL9 gene, and to a lesser extent the CXCL10 gene in LCM, the absence of the IFN-gamma receptor did not influence the disease outcome. This finding suggested that these chemokines may not play a major role in the pathogenesis of LCM. To evaluate this possibility further the development of LCM was examined in mice that were deficient for CXCR3. Surprisingly, in the absence of CXCR3 there was no alteration in mortality, cytokine expression, or T cell infiltration in the CNS, demonstrating that in contrast to LCMV-Traub, CXCR3 is not involved in the pathogenesis of LCMV-Armstrong-induced neurological disease in mice. Our findings indicate that despite similar immunopathogenetic mechanisms involving antiviral CD8(+) T cells, whether or not CXCR3 signaling has a role in LCM is dependent upon the infecting strain of LCMV.
%Z FOR Codes: 110799


%0 Journal Article
%~ PubMed
%A Müller, Marcus
%A Carter, Sally L
%A Hofer, Markus J
%A Manders, Peter
%A Getts, Daniel R
%A Getts, Meghan T
%A Dreykluft, Angela
%A Lu, Bao
%A Gerard, Craig
%A King, Nicholas J C
%A Campbell, Iain L
%T CXCR3 Signaling Reduces the Severity of Experimental Autoimmune Encephalomyelitis by Controlling the Parenchymal Distribution of Effector and Regulatory T Cells in the Central Nervous System.
%B Journal of immunology (Baltimore, Md. : 1950)
%D 2007
%C United States
%I American Association of Immunologists
%V 179
%N 5
%P 2774-2786
%@ 0022-1767
%X The chemokine receptor CXCR3 promotes the trafficking of activated T and NK cells in response to three ligands, CXCL9, CXCL10, and CXCL11. Although these chemokines are produced in the CNS in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), their role in the pathogenesis of CNS autoimmunity is unresolved. We examined the function of CXCR3 signaling in EAE using mice that were deficient for CXCR3 (CXCR3(-/-)). The time to onset and peak disease severity were similar for CXCR3(-/-) and wild-type (WT) animals; however, CXCR3(-/-) mice had more severe chronic disease with increased demyelination and axonal damage. The inflammatory lesions in WT mice consisted of well-demarcated perivascular mononuclear cell infiltrates, mainly in the spinal cord and cerebellum. In CXCR3(-/-) mice, these lesions were more widespread throughout the CNS and were diffused and poorly organized, with T cells and highly activated microglia/macrophages scattered throughout the white matter. Although the number of CD4(+) and CD8(+) T cells infiltrating the CNS were similar in CXCR3(-/-) and WT mice, Foxp3(+) regulatory T cells were significantly reduced in number and dispersed in CXCR3(-/-) mice. The expression of various chemokine and cytokine genes in the CNS was similar in CXCR3(-/-) and WT mice. The genes for the CXCR3 ligands were expressed predominantly in and/or immediately surrounding the mononuclear cell infiltrates. We conclude that in EAE, CXCR3 signaling constrains T cells to the perivascular space in the CNS and augments regulatory T cell recruitment and effector T cell interaction, thus limiting autoimmune-mediated tissue damage.
%Z FOR Codes: 110704


%0 Journal Article
%~ PubMed
%A Quintana, Albert
%A Molinero, Amalia
%A Florit, Sergi
%A Manso, Yasmina
%A Comes, Gemma
%A Carrasco, Javier
%A Giralt, Mercedes
%A Borup, Rehannah
%A Nielsen, Finn Cilius
%A Campbell, Iain L
%A Penkowa, Milena
%A Hidalgo, Juan
%T Diverging mechanisms for TNF-alpha receptors in normal mouse brains and in functional recovery after injury: From gene to behavior.
%B Journal of neuroscience research
%D 2007
%C United States
%I Wiley Interscience
%V 85
%N 12
%P 2668-85
%@ 0360-4012
%X Cytokines, such as tumour necrosis factor (TNF)-alpha and lymphotoxin-alpha, have been described widely to play important roles in the brain in physiologic conditions and after traumatic injury. However, the exact mechanisms involved in their function have not been fully elucidated. We give some insight on their role by using animals lacking either Type 1 receptor (TNFR1KO) or Type 2 (TNFR2KO) and their controls (C57Bl/6). Both TNFR1KO and to a greater extent TNFR2KO mice showed increased exploration/activity neurobehavioral traits in the hole board test, such as rearings, head dippings, and ambulations, compared with wild-type mice, suggesting an inhibitory role of TNFR1/TNFR2 signaling. In contrast, no significant differences were observed in the elevated plus maze test, ruling out a major role of these receptors in the control of anxiety. We next evaluated the response to a freeze injury to the somatosensorial cortex. The effect of the cryolesion on motor function was evaluated with the horizontal ladder beam test, and the results showed that both TNFR1KO and TNFR2KO mice made fewer errors, suggesting a detrimental role for TNFR1/TNFR2 signaling for coping with brain damage. Expression of approximately 22600 genes was analyzed using an Affymetrix chip (MOE430A) at 0 (unlesioned), 1, or 4 days post-lesion in the three strains. The results show a unique and major role of both TNF receptors on the pattern of gene expression elicited by the injury but also in normal conditions, and suggest that blocking of TNFR1/TNFR2 receptors may be beneficial after a traumatic brain injury. (c) 2006 Wiley-Liss, Inc.
%Z FOR Codes: 110703 110903


%0 Journal Article
%~ PubMed
%A Carr, Daniel J J
%A Campbell, Iain L
%T Herpes simplex virus type 1 induction of chemokine production is unrelated to viral load in the cornea but not in the nervous system.
%B Viral immunology
%D 2007
%C United States
%I Mary Ann Liebert, Inc. Publishers
%V 19
%N 4
%P 741-6
%@ 0882-8245
%X Herpes simplex virus type 1 elicits a strong host inflammatory response after corneal infection. The purpose of the current study was to compare the production of chemokines induced by viral infection at sites known to harbor virus after ocular inoculation in order to determine the relationship between viral load and chemokine expression. Using highly resistant IFN-alpha1 transgenic mice whose transgene is under the control of the glial fibrillary acidic protein promoter in comparison with the more sensitive wild-type counterparts, we compared the expression of chemokines versus the amount of infectious virus recovered from the anterior segment of the eye and nervous system. Consistent with our predicted outcome, the level of infectious virus recovered in the iris, trigeminal ganglia, and brainstem of resistant versus sensitive mice correlated with chemokine production; that is, the less virus recovered the less chemokine (CCL2, CCL3, CCL5, CXCL9, and CXCL10) produced. In contrast to the nervous system and iris, there was no correlation between chemokine expression and level of infectious virus recovered in the cornea. We interpret these results as suggesting chemokine expression within the cornea in response to herpes simplex virus type 1 infection is driven by factors other than antigenic stimulation.
%Z FOR Codes: 110702


%0 Journal Article
%~ PubMed
%A Millward, Jason M
%A Caruso, Maria
%A Campbell, Iain L
%A Gauldie, Jack
%A Owens, Trevor
%T IFN-gamma-induced chemokines synergize with pertussis toxin to promote T cell entry to the central nervous system.
%B Journal of immunology (Baltimore, Md. : 1950)
%D 2007
%C United States
%I American Association of Immunologists
%V 178
%N 12
%P 8175-8182
%@ 0022-1767
%X Inflammation of the CNS, which occurs during multiple sclerosis and experimental autoimmune encephalomyelitis, is characterized by increased levels of IFN-gamma, a cytokine not normally expressed in the CNS. To investigate the role of IFN-gamma in CNS, we used intrathecal injection of a replication-defective adenovirus encoding murine IFN-gamma (AdIFNgamma) to IFN-gamma-deficient (GKO) mice. This method resulted in stable, long-lived expression of IFN-gamma that could be detected in cerebrospinal fluid using ELISA and Luminex bead immunoassay. IFN-gamma induced expression in the CNS of message and protein for the chemokines CXCL10 and CCL5, to levels comparable to those seen during experimental autoimmune encephalomyelitis. Other chemokines (CXCL2, CCL2, CCL3) were not induced. Mice lacking the IFN-gammaR showed no response, and a control viral vector did not induce chemokine expression. Chemokine expression was predominantly localized to meningeal and ependymal cells, and was also seen in astrocytes and microglia. IFN-gamma-induced chemokine expression did not lead to inflammation. However, when pertussis toxin was given i.p. to mice infected with the IFN-gamma vector, there was a dramatic increase in the number of T lymphocytes detected in the CNS by flow cytometry. This increase in blood-derived immune cells in the CNS did not occur with pertussis toxin alone, and did not manifest as histologically detectable inflammatory pathology. These results show that IFN-gamma induces a characteristic glial chemokine response that by itself is insufficient to promote inflammation, and that IFN-gamma-induced CNS chemoattractant signals can synergize with a peripheral infectious stimulus to drive T cell entry into the CNS.
%Z FOR Codes: 110703 110903


%0 Journal Article
%~ PubMed
%A Carter, Sally L
%A Müller, Marcus
%A Manders, Peter M
%A Campbell, Iain L
%T Induction of the genes for Cxcl9 and Cxcl10 is dependent on IFN-gamma but shows differential cellular expression in experimental autoimmune encephalomyelitis and by astrocytes and microglia in vitro.
%B Glia
%D 2007
%C United States
%I Wiley-Liss
%V 55
%N 16
%P 1728-39
%@ 0894-1491
%X The chemokines CXCL9 and CXCL10 bind to the common receptor CXCR3 and are implicated in the pathogenesis of T-cell-mediated immunity in the central nervous system (CNS). Here we examined the temporal and spatial regulation of the Cxcl9 and Cxcl10 genes in the CNS of mice with myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and by glial cells in vitro. During peak disease the levels of CXCL9 and CXCL10 mRNA and protein were increased significantly in the cerebellum and spinal cord but were reduced during the recovery phase. Expression of these genes in the CNS was abolished in IFN-gamma-receptor deficient mice with MOG-EAE. In wild-type mice, CXCL9 RNA was localized mainly to infiltrating mononuclear cells including lesion and perilesional microglia, while CXCL10 RNA was seen primarily in more distal astrocytes that surrounded the inflammatory lesions. Examination of cultured glia following treatment with IFN-gamma revealed that while both CXCL9 and CXCL10 mRNA transcripts were induced in microglia, only CXCL10 mRNA was induced in astrocytes. Thus, although IFN-gamma is the pivotal mediator of both Cxcl10 and Cxcl9 gene expression in EAE, this cytokine differentially regulates the expression of these genes by astrocytes and microglia. The differential glial localization of these chemokines in EAE suggests CXCL9 and CXCL10 have specialized functions.
%Z FOR Codes: 110703 110903


%0 Journal Article
%~ Isi
%A Hofer, MJ
%A Mueller, M
%A OSullivan, C
%A Manders, P
%A Campbell, IL
%T Lethal lymphocytic choriomeningitis virus (LCMV) infection in STAT1 KO mice is associated with dysregulated PD-1/B7-H1 and a phenotypic switch in the T-cell response
%B JOURNAL OF INTERFERON AND CYTOKINE RESEARCH
%D 2007
%C United Kingdom
%I Mary Ann Liebert, Inc. Publishers
%V 27
%N 8
%P 696-696
%@ 1079-9907
%X 
%Z FOR Codes:


%0 Journal Article
%~ PubMed
%A Getts, Daniel R
%A Matsumoto, Izuru
%A Müller, Marcus
%A Getts, Meghann Teague
%A Radford, Jane
%A Shrestha, Bimmi
%A Campbell, Iain L
%A King, Nicholas J C
%T Role of IFN-gamma in an experimental murine model of West Nile virus-induced seizures.
%B Journal of neurochemistry
%D 2007
%C UK
%I Blackwell Publishing Ltd
%V 103
%N 3
%P 1019-30
%@ 1471-4159
%X Seizures are a major complication of viral encephalitis. However, the mechanisms of seizure-associated neuronal dysfunction remain poorly understood. We report that intranasal inoculation with West Nile virus (WNV) (Sarafend) causes limbic seizures in C57BL/6 mice, but not in interferon (IFN)-gamma-deficient (IFN-gamma-/-) mice. Both strains showed similar levels of virus in the brain, as well as similar concentrations of the cytokines, tumor necrosis factor and interleukin-6, both of which can alter neuronal excitability. Experiments in chimeric IFN-gamma-/- mice reconstituted with IFN-gamma-producing leukocytes showed that IFN-gamma is not required during central nervous system infection for limbic seizure development, suggesting a role for IFN-gamma in the developing brain. This was supported responses to pentylenetetrazole, kainic acid (KA), and N-methyl-d-aspartate (NMDA). Both strains of mice exhibited similar behavior after pentylenetetrazole challenge. However, while NMDA and KA treatment resulted in characteristic seizures in C57BL/6 mice, these responses were diminished (NMDA treatment) or absent (KA treatment) in IFN-gamma-/- mice. Furthermore, NMDA-receptor blockade with MK-801 in WNV-infected C57BL/6 mice abrogated seizures and prolonged survival. Our data show that IFN-gamma plays an important role in the development of the excitatory seizure pathways in the brain and that these cascades become pathogenic in encephalitic WNV infection.
%Z FOR Codes: 110704 110903 110804


%0 Journal Article
%~ Isi
%A Campbell, IL
%A Iglesias, ES
%A Unzeta, M
%T STAT1 has a minimal role in interleukin-6 signalling and actions in the murine brain
%B JOURNAL OF INTERFERON AND CYTOKINE RESEARCH
%D 2007
%C United States
%I Mary Ann Liebert, Inc. Publishers
%V 27
%N 8
%P 722-722
%@ 1079-9907
%X 
%Z FOR Codes:


%0 Journal Article
%~ Isi
%A Crocker, S. J.
%A Milner, R.
%A Pham-Mitchell, N.
%A Campbell, I. L.
%T Cell and agonist-specific regulation of genes for matrix metalloproteinases and their tissue inhibitors by primary glial cells.
%B Journal of Neurochemistry
%D 2006
%C OXFORD, ENGLAND
%I Blackwell Publishing Ltd.
%V 98
%N 3
%P 812-823
%@ 0022-3042
%X 
%Z FOR Codes: 110702


%0 Journal Article
%~ PubMed
%A Wacher, Christie
%A Müller, Marcus
%A Hofer, Markus J
%A Getts, Daniel R
%A Zabaras, Regina
%A Ousman, Shalina S
%A Terenzi, Fulvia
%A Sen, Ganes C
%A King, Nicholas J C
%A Campbell, Iain L
%T Co-ordinate regulation and widespread cellular expression of the interferon stimulated genes (ISG)-49, ISG-54 and ISG-56 in the central nervous system following infection with distinct viruses.
%B Journal of virology
%D 2006
%C US
%I American Society for Microbiology
%V 81
%N 2
%P 860-71
%@ 0022-538X
%X The interferon (IFN)-stimulated genes (ISGs) ISG-49, ISG-54, and ISG-56 are highly responsive to viral infection, yet the regulation and function of these genes in vivo are unknown. We examined the simultaneous regulation of these ISGs in the brains of mice during infection with either lymphocytic choriomeningitis virus (LCMV) or West Nile virus (WNV). Expression of the ISG-49 and ISG-56 genes increased significantly during LCMV infection, being widespread and localized predominantly to common as well as distinct neuronal populations. Expression of the ISG-54 gene also increased but to lower levels and with a more restricted distribution. Although expression of the ISG-49, ISG-54, and ISG-56 genes was increased in the brains of LCMV-infected STAT1 and STAT2 knockout (KO) mice, this was blunted, delayed, and restricted to the choroid plexus, meninges, and endothelium. ISG-56 protein was regulated in parallel with the corresponding RNA transcript in the brain during LCMV infection in wild-type and STAT KO mice. Similar changes in ISG-49, ISG-54, and ISG-56 RNA levels and ISG-56 protein levels were observed in the brains of wild-type mice following infection with WNV. Thus, the ISG-49, ISG-54, and ISG-56 genes are coordinately upregulated in the brain during LCMV and WNV infection; this upregulation, in the case of LCMV, was totally (neurons) or partially (non-neurons) dependent on the IFN-signaling molecules STAT1 and STAT2. These findings suggest a dominant role for the ISG-49, ISG-54, and ISG-56 genes in the host response to different viruses in the central nervous system, where, particularly in neurons, these genes may have nonredundant functions.
%Z FOR Codes: 110804


%0 Journal Article
%~ PubMed
%A Milner, Richard
%A Campbell, Iain L
%T Increased expression of the beta4 and alpha5 integrin subunits in cerebral blood vessels of transgenic mice chronically producing the pro-inflammatory cytokines IL-6 or IFN-alpha in the central nervous system.
%B Molecular and cellular neurosciences
%D 2006
%C SAN DIEGO, USA
%I Academic Press
%V 33
%N 4
%P 429-40
%@ 1044-7431
%X Evidence suggests that vascular function is strongly regulated by extracellular matrix (ECM) proteins via integrin-mediated signaling. To determine whether integrin expression on cerebral blood vessels is altered during chronic neuroinflammation, we examined beta1 and beta4 integrin expression in transgenic mice with astrocyte production of the pro-inflammatory cytokines interleukin-6 (IL-6) or interferon-alpha (IFN-alpha). Chronic production of IL-6 or IFN-alpha in the CNS promoted vascular expression of the beta4 and alpha5 integrin subunits, and this was contributed mostly by astrocytes. Vascular expression of the ECM ligands laminin and fibronectin was also increased. Cell culture studies showed that astrocyte expression of the beta4 and alpha5 integrins was significantly upregulated by IL-6 and IFN-alpha, respectively, while endothelial expression of these integrins was unchanged. These results show that astrocytes respond to IL-6 and IFN-alpha by upregulating integrin expression. We propose that during neuroinflammation, astrocytes attempt to increase adhesive interactions at the blood-brain barrier (BBB), in order to increase barrier integrity.
%Z FOR Codes: 110702


%0 Journal Article
%~ Isi
%A Crocker, S. J.
%A Whitmire, J. K.
%A Frausto, R. F.
%A Chertboonmuang, P.
%A Soloway, P. D.
%A Whitton, J. L.
%A Campbell, I. L.
%T Persistent macrophage/microglial activation and myelin disruption after experimental autoimmune encephalomyelitis in tissue inhibitor of metalloproteinase-1-deficient mice.
%B American Journal of Pathology
%D 2006
%C Inc, 9650 Rockville
%I Amer Soc Investigative Pathology
%V 169
%N 6
%P 2104-2116
%@ 0002-9440
%X 
%Z FOR Codes: 110703


%0 Journal Article
%~ Isi
%A Zirger, J. M.
%A Barcia, C.
%A Liu, C. Y.
%A Puntel, M.
%A Mitchell, N.
%A Campbell, I.
%A Castro, M.
%A Lowenstein, P. R.
%T Rapid upregulation of interferon-regulated and chemokine mRNAs upon injection of 10(8) international units, but not lower doses, of adenoviral vectors into the brain.
%B Journal of Virology
%D 2006
%C US
%I American Society for Microbiology
%V 80
%N 11
%P 5655-5659
%@ 0022-538X
%X 
%Z FOR Codes: 110704