Maturation and Localization of Macrophages and Microglia During Infection with a Neurotropic Murine Coronavirus

Templeton, Steven P.; Kim, Taeg S.; O’Malley, Katherine J.; Perlman, Stanley

doi:10.1111/j.1750-3639.2007.00098.x

Cited by 56 publications

(56 citation statements)

References 51 publications

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“…Furthermore, the majority of the CD11b ϩ infiltrating cells had the Ly-6C hi phenotype ( Fig. 1E), which was recently established as a reliable marker of blood-derived macrophages (1,99,100). Taken together, these data suggest that the CNS of me/me mice displays a dramatic increase in the number of infiltrating macrophages (7,41,58,88).…”

Section: Resultssupporting

confidence: 55%

Modulation of Macrophage Infiltration and Inflammatory Activity by the Phosphatase SHP-1 in Virus-Induced Demyelinating Disease

Christophi

Hudson

Panos³

et al. 2009

J Virol

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The protein tyrosine phosphatase SHP-1 is a crucial negative regulator of cytokine signaling and inflammatory gene expression, both in the immune system and in the central nervous system (CNS). Mice genetically lacking SHP-1 (me/me) display severe inflammatory demyelinating disease following inoculation with the Theiler's murine encephalomyelitis virus (TMEV) compared to infected wild-type mice. Therefore, it became essential to investigate the mechanisms of TMEV-induced inflammation in the CNS of SHP-1-deficient mice. Herein, we show that the expression of several genes relevant to inflammatory demyelination in the CNS of infected me/me mice is elevated compared to that in wild-type mice. Furthermore, SHP-1 deficiency led to an abundant and exclusive increase in the infiltration of high-level-CD45-expressing (CD45 hi ) CD11b Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) that remains a major cause of disability (76). Several studies demonstrated that MS lesions contain multiple leukocyte cell types, including lymphocytes, macrophages, and dendritic cells, all of which are believed to contribute to lesion formation by various distinct and interacting mechanisms (54, 61). Among these leukocyte subsets, infiltrating macrophages have been identified as major effectors of demyelination in both MS and animal models for MS (17,44,59,102). In accord with these studies, it was recently reported that the dominant mechanism of demyelination in MS is macrophage mediated (15). Indeed, in some models for MS, the requirement for lymphocytes is negligible and macrophages are the sole mediators of demyelination (6, 72).These findings have stimulated intense interest in the function of macrophages in lesion formation, including signaling events that draw these cells into the CNS white matter and trigger the effector mechanisms by which these cells damage myelin. For instance, macrophages have been identified as the major responders to CNS chemokines and producers of a number of proinflammatory cytokines, chemokines, and toxic molecules known to promote demyelination (32,44,63,85,90,91,93,103). Interestingly, both the brains of MS patients and the brains of experimental animals with MS-like diseases contain activated transcription factors like NF-B (34, 40), STAT1 (35,37,40), and STAT6 (18,21,109), which can lead to enhanced expression of these inflammatory molecules. Based on the findings of our previous work, we propose that the modulation of inflammatory signaling via these transcriptional pathways may be deficient in the leukocytes, including the macrophages, of MS patients and that this deficiency is responsible for susceptibility to inflammatory demyelinating processes within the CNS.SHP-1 is a protein tyrosine phosphatase with two Src homology 2 domains which acts as a negative regulator of both innate and acquired immune cytokine signaling via NF-B (52, 67), STAT1 (29,68), and STAT6 (13,43,45,50). Mice genetically lacking SHP-1 (motheaten mice) display myelin de...

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Section: Resultssupporting

confidence: 55%

Modulation of Macrophage Infiltration and Inflammatory Activity by the Phosphatase SHP-1 in Virus-Induced Demyelinating Disease

Christophi

Hudson

Panos³

et al. 2009

J Virol

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“…The Ly-6C hi monocytes migrated to the inflamed/necrotic area and subsequently differentiated into mature macrophages. This process required downregulation of Ly-6C expression and an increase in the expression of the mature macrophage marker F4/80 (2,38). In the present study, we demonstrated that the loss of Foxm1 in a myeloid lineage reduced numbers of Ly-6C lo /F4/80 hi mature macrophages at 72 h after liver injury, coinciding with delayed liver repair.…”

Section: Discussionmentioning

confidence: 54%

Forkhead Box M1 Transcription Factor Is Required for Macrophage Recruitment during Liver Repair

Ren¹,

Zhang²,

Snyder³

et al. 2010

Molecular and Cellular Biology

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Acute liver injury results from exposure to toxins, pharmacological agents, or viral infections, contributing to significant morbidity and mortality worldwide. While hepatic inflammation is critical for liver repair, the transcriptional mechanisms required for the recruitment of inflammatory cells to the liver are not understood. Forkhead box M1 (Foxm1) transcription factor is a master regulator of hepatocyte proliferation, but its role in inflammatory cells remains unknown. In this study, we generated transgenic mice in which Foxm1 was deleted from myeloid-derived cells, including macrophages, monocytes, and neutrophils. Carbon tetrachloride liver injury was used to demonstrate that myeloid-specific Foxm1 deletion caused a delay in liver repair. Although Foxm1 deficiency did not influence neutrophil infiltration into injured livers, the total numbers of mature macrophages were dramatically reduced. Surprisingly, Foxm1 deficiency did not influence the proliferation of macrophages or their monocytic precursors but impaired monocyte recruitment during liver repair. Expression of L-selectin and the CCR2 chemokine receptor, both critical for monocyte recruitment to injured tissues, was decreased. Foxm1 induced transcriptional activity of the mouse CCR2 promoter in cotransfection experiments. Adoptive transfer of monocytes to Foxm1-deficient mice restored liver repair and rescued liver function. Foxm1 is critical for liver repair and is required for the recruitment of monocytes to the injured liver.

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“…Whereas neutrophils, characterized as CD45 hi Ly6C low F4/80 Ϫ Ly6G hi (6,45), represented a small percentage of CNS infiltrating leukocytes following infection (Fig. 1A) (ϳ6% at day 3 p.i.…”

Section: Inflammatory Monocytes Dominate Cns Inflammatory Cells Earlymentioning

confidence: 99%

Monocytes Regulate T Cell Migration through the Glia Limitans during Acute Viral Encephalitis

Savarin

Stohlman

Atkinson

et al. 2010

J Virol

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Leukocyte access into the central nervous system (CNS) parenchyma is tightly regulated by the bloodbrain barrier (BBB). Leukocyte migration through the endothelial cell wall into the perivascular space is well characterized; however, mechanisms regulating their penetration through the glia limitans into the parenchyma are less well studied, and the role of monocytes relative to neutrophils is poorly defined. Acute viral encephalitis was thus induced in CCL2-deficient (CCL2 ؊/؊ ) mice to specifically abrogate monocyte recruitment. Impaired monocyte recruitment prolonged T cell retention in the perivascular space, although no difference in overall CNS accumulation of CD4 or CD8 T cells was detected by flow cytometry. Delayed penetration to the CNS parenchyma was not associated with reduced or altered expression of either matrix metalloproteinases (MMP) or the T cell chemoattractants CXCL10 and CCL5. Nevertheless, decreased parenchymal leukocyte infiltration delayed T cell-mediated control of virus replication as well as clinical disease. These data are the first to demonstrate that the rapid monocyte recruitment into the CNS during viral encephalitis is dispensable for T cell migration across the blood vessel endothelium. However, monocytes facilitate penetration through the glia limitans. Thus, the rapid monocyte response to viral encephalitis constitutes an indirect antiviral pathway by aiding access of effector T cells to the site of viral infection.

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Maturation and Localization of Macrophages and Microglia During Infection with a Neurotropic Murine Coronavirus

Cited by 56 publications

References 51 publications

Modulation of Macrophage Infiltration and Inflammatory Activity by the Phosphatase SHP-1 in Virus-Induced Demyelinating Disease

Modulation of Macrophage Infiltration and Inflammatory Activity by the Phosphatase SHP-1 in Virus-Induced Demyelinating Disease

Forkhead Box M1 Transcription Factor Is Required for Macrophage Recruitment during Liver Repair

Monocytes Regulate T Cell Migration through the Glia Limitans during Acute Viral Encephalitis

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