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Negative regulation of autoimmune demyelination by the inhibitory receptor CLM-1.

Xi H, Katschke KJ, Helmy KY, Wark PA, Kljavin N, Clark H, Eastham-Anderson J, Shek T, Roose-Girma M, Ghilardi N, van Lookeren Campagne M - J. Exp. Med. (2009)

Bottom Line: CLM-1 is expressed on inflammatory myeloid cells present in demyelinating areas of the spinal cord after immunization of mice with MOG35-55 (myelin oligodendrocyte glycoprotein) peptide.Absence of CLM-1 resulted in significantly increased nitric oxide and proinflammatory cytokine production, along with increased demyelination and worsened clinical scores, whereas T cell responses in the periphery or in the spinal cord remained unaffected.This study thus identifies CLM-1 as a negative regulator of myeloid effector cells in autoimmune demyelination.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.

ABSTRACT
Multiple sclerosis and its preclinical model, experimental autoimmune encephalomyelitis, are marked by perivascular inflammation and demyelination. Myeloid cells, derived from circulating progenitors, are a prominent component of the inflammatory infiltrate and are believed to directly contribute to demyelination and axonal damage. How the cytotoxic activity of these myeloid cells is regulated is poorly understood. We identify CMRF-35-like molecule-1 (CLM-1) as a negative regulator of autoimmune demyelination. CLM-1 is expressed on inflammatory myeloid cells present in demyelinating areas of the spinal cord after immunization of mice with MOG35-55 (myelin oligodendrocyte glycoprotein) peptide. Absence of CLM-1 resulted in significantly increased nitric oxide and proinflammatory cytokine production, along with increased demyelination and worsened clinical scores, whereas T cell responses in the periphery or in the spinal cord remained unaffected. This study thus identifies CLM-1 as a negative regulator of myeloid effector cells in autoimmune demyelination.

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CLM-1 is expressed on myeloid cells in CNS inflammatory lesions. (A) CLM-1 mRNA expression in spinal cord after MOG35-55 immunization. Fold induction is calculated based on day 0 values. Values are expressed as means ± SEM. (B) CLM-1 expression on CD11b+CD11c+ cells in the spinal cord of naive and MOG35-55-immunized mice. (C) Clusters of CLM-1+ CD11c+ myeloid cells in the ventrolateral funiculi and adjacent to leptomeninges (dotted line) of the cervical spinal cord (rectangle enlarged in middle and right). Bar, 10 µm. (D) TNF, iNOS, and CLM-1 expression on CD45loCD11b+-resident microglia (top row) and on CD45hiCD11b+-infiltrating BM-derived cells. Open histograms represent antigen-specific staining and shaded histograms represent isotype control. Results shown are from one experiment out of three, with five (A), three (C), or two (B and D) mice per experimental group.
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fig1: CLM-1 is expressed on myeloid cells in CNS inflammatory lesions. (A) CLM-1 mRNA expression in spinal cord after MOG35-55 immunization. Fold induction is calculated based on day 0 values. Values are expressed as means ± SEM. (B) CLM-1 expression on CD11b+CD11c+ cells in the spinal cord of naive and MOG35-55-immunized mice. (C) Clusters of CLM-1+ CD11c+ myeloid cells in the ventrolateral funiculi and adjacent to leptomeninges (dotted line) of the cervical spinal cord (rectangle enlarged in middle and right). Bar, 10 µm. (D) TNF, iNOS, and CLM-1 expression on CD45loCD11b+-resident microglia (top row) and on CD45hiCD11b+-infiltrating BM-derived cells. Open histograms represent antigen-specific staining and shaded histograms represent isotype control. Results shown are from one experiment out of three, with five (A), three (C), or two (B and D) mice per experimental group.

Mentions: A genome-wide search was performed to identify single transmembrane Ig superfamily members containing an ITIM (Yu et al., 2009). Mouse homologues of the candidate ITIM-containing genes were then selected based on their specific expression on myeloid cells and expression levels in the spinal cord after immunization with MOG35-55 peptide. Of all candidate ITIM genes, CLM-1 messenger RNA (mRNA) levels showed the highest fold increase (>1,500-fold) relative to naive mice at 2 wk after immunization (Fig. 1 A). Monoclonal antibodies to CLM-1 extracellular domain (ECD) were generated to determine the cellular source of CLM-1. CLM-1 was absent on the CD11b+ local microglia population in naive mice (Fig. 1 B, left). In spinal cords from MOG-immunized mice, CLM-1 was highly expressed on CD11b+CD11c+ myeloid cells that also expressed MHC class II, CD86, and Gr-1 (Fig. 1 B, right; and Fig. S1 B). Immunohistochemical studies further illustrated that CLM-1+CD11c+ cells appear in clusters located predominantly in the ventrolateral funiculi of the cervical spinal cord (Fig. 1 C). Although CNS-resident CD45loCD11b+CD11c− microglia cells did not express CLM-1 and iNOS and expressed low levels of TNF, CD45hiCD11b+ BM-derived myeloid cells present in spinal cord at the onset and peak of disease expressed CLM-1, iNOS, and TNF (Fig. 1 D). A subset of CLM-1+ cells also expressed CD11c and, therefore, displayed characteristics of the TNF- and iNOS-producing (Tip) DCs that were originally described by Serbina et al. (2003).


Negative regulation of autoimmune demyelination by the inhibitory receptor CLM-1.

Xi H, Katschke KJ, Helmy KY, Wark PA, Kljavin N, Clark H, Eastham-Anderson J, Shek T, Roose-Girma M, Ghilardi N, van Lookeren Campagne M - J. Exp. Med. (2009)

CLM-1 is expressed on myeloid cells in CNS inflammatory lesions. (A) CLM-1 mRNA expression in spinal cord after MOG35-55 immunization. Fold induction is calculated based on day 0 values. Values are expressed as means ± SEM. (B) CLM-1 expression on CD11b+CD11c+ cells in the spinal cord of naive and MOG35-55-immunized mice. (C) Clusters of CLM-1+ CD11c+ myeloid cells in the ventrolateral funiculi and adjacent to leptomeninges (dotted line) of the cervical spinal cord (rectangle enlarged in middle and right). Bar, 10 µm. (D) TNF, iNOS, and CLM-1 expression on CD45loCD11b+-resident microglia (top row) and on CD45hiCD11b+-infiltrating BM-derived cells. Open histograms represent antigen-specific staining and shaded histograms represent isotype control. Results shown are from one experiment out of three, with five (A), three (C), or two (B and D) mice per experimental group.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2812551&req=5

fig1: CLM-1 is expressed on myeloid cells in CNS inflammatory lesions. (A) CLM-1 mRNA expression in spinal cord after MOG35-55 immunization. Fold induction is calculated based on day 0 values. Values are expressed as means ± SEM. (B) CLM-1 expression on CD11b+CD11c+ cells in the spinal cord of naive and MOG35-55-immunized mice. (C) Clusters of CLM-1+ CD11c+ myeloid cells in the ventrolateral funiculi and adjacent to leptomeninges (dotted line) of the cervical spinal cord (rectangle enlarged in middle and right). Bar, 10 µm. (D) TNF, iNOS, and CLM-1 expression on CD45loCD11b+-resident microglia (top row) and on CD45hiCD11b+-infiltrating BM-derived cells. Open histograms represent antigen-specific staining and shaded histograms represent isotype control. Results shown are from one experiment out of three, with five (A), three (C), or two (B and D) mice per experimental group.
Mentions: A genome-wide search was performed to identify single transmembrane Ig superfamily members containing an ITIM (Yu et al., 2009). Mouse homologues of the candidate ITIM-containing genes were then selected based on their specific expression on myeloid cells and expression levels in the spinal cord after immunization with MOG35-55 peptide. Of all candidate ITIM genes, CLM-1 messenger RNA (mRNA) levels showed the highest fold increase (>1,500-fold) relative to naive mice at 2 wk after immunization (Fig. 1 A). Monoclonal antibodies to CLM-1 extracellular domain (ECD) were generated to determine the cellular source of CLM-1. CLM-1 was absent on the CD11b+ local microglia population in naive mice (Fig. 1 B, left). In spinal cords from MOG-immunized mice, CLM-1 was highly expressed on CD11b+CD11c+ myeloid cells that also expressed MHC class II, CD86, and Gr-1 (Fig. 1 B, right; and Fig. S1 B). Immunohistochemical studies further illustrated that CLM-1+CD11c+ cells appear in clusters located predominantly in the ventrolateral funiculi of the cervical spinal cord (Fig. 1 C). Although CNS-resident CD45loCD11b+CD11c− microglia cells did not express CLM-1 and iNOS and expressed low levels of TNF, CD45hiCD11b+ BM-derived myeloid cells present in spinal cord at the onset and peak of disease expressed CLM-1, iNOS, and TNF (Fig. 1 D). A subset of CLM-1+ cells also expressed CD11c and, therefore, displayed characteristics of the TNF- and iNOS-producing (Tip) DCs that were originally described by Serbina et al. (2003).

Bottom Line: CLM-1 is expressed on inflammatory myeloid cells present in demyelinating areas of the spinal cord after immunization of mice with MOG35-55 (myelin oligodendrocyte glycoprotein) peptide.Absence of CLM-1 resulted in significantly increased nitric oxide and proinflammatory cytokine production, along with increased demyelination and worsened clinical scores, whereas T cell responses in the periphery or in the spinal cord remained unaffected.This study thus identifies CLM-1 as a negative regulator of myeloid effector cells in autoimmune demyelination.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunology, Genentech Inc., South San Francisco, CA 94080, USA.

ABSTRACT
Multiple sclerosis and its preclinical model, experimental autoimmune encephalomyelitis, are marked by perivascular inflammation and demyelination. Myeloid cells, derived from circulating progenitors, are a prominent component of the inflammatory infiltrate and are believed to directly contribute to demyelination and axonal damage. How the cytotoxic activity of these myeloid cells is regulated is poorly understood. We identify CMRF-35-like molecule-1 (CLM-1) as a negative regulator of autoimmune demyelination. CLM-1 is expressed on inflammatory myeloid cells present in demyelinating areas of the spinal cord after immunization of mice with MOG35-55 (myelin oligodendrocyte glycoprotein) peptide. Absence of CLM-1 resulted in significantly increased nitric oxide and proinflammatory cytokine production, along with increased demyelination and worsened clinical scores, whereas T cell responses in the periphery or in the spinal cord remained unaffected. This study thus identifies CLM-1 as a negative regulator of myeloid effector cells in autoimmune demyelination.

Show MeSH
Related in: MedlinePlus