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LRP1 expression in microglia is protective during CNS autoimmunity.

Chuang TY, Guo Y, Seki SM, Rosen AM, Johanson DM, Mandell JW, Lucchinetti CF, Gaultier A - Acta Neuropathol Commun (2016)

Bottom Line: While T cells are known orchestrators of the immune response leading to MS pathology, the precise contribution of CNS resident and peripheral infiltrating myeloid cells is less well described.We further show that the increased disease severity in experimental autoimmune encephalomyelitis is not due to haplodeficiency of the Cx3cr1 locus.At the cellular level, microglia lacking LRP1 adopt a pro-inflammatory phenotype characterized by amoeboid morphology and increased production of the inflammatory mediator TNF-α.

View Article: PubMed Central - PubMed

Affiliation: Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.

ABSTRACT
Multiple sclerosis is a devastating neurological disorder characterized by the autoimmune destruction of the central nervous system myelin. While T cells are known orchestrators of the immune response leading to MS pathology, the precise contribution of CNS resident and peripheral infiltrating myeloid cells is less well described. Here, we explore the myeloid cell function of Low-density lipoprotein receptor-related protein-1 (LRP1), a scavenger receptor involved in myelin clearance and the inflammatory response, in the context of Multiple sclerosis. Supporting its central role in Multiple sclerosis pathology, we find that LRP1 expression is increased in Multiple sclerosis lesions in comparison to the surrounding healthy tissue. Using two genetic mouse models, we show that deletion of LRP1 in microglia, but not in peripheral macrophages, negatively impacts the progression of experimental autoimmune encephalomyelitis, an animal model of Multiple sclerosis. We further show that the increased disease severity in experimental autoimmune encephalomyelitis is not due to haplodeficiency of the Cx3cr1 locus. At the cellular level, microglia lacking LRP1 adopt a pro-inflammatory phenotype characterized by amoeboid morphology and increased production of the inflammatory mediator TNF-α. We also show that LRP1 functions as a robust inhibitor of NF-kB activation in myeloid cells via a MyD88 dependent pathway, potentially explaining the increase in disease severity observed in mice lacking LRP1 expression in microglia. Taken together, our data suggest that the function of LRP1 in microglia is to keep these cells in an anti-inflammatory and neuroprotective status during inflammatory insult, including experimental autoimmune encephalomyelitis and potentially in Multiple sclerosis.

No MeSH data available.


Related in: MedlinePlus

Deletion of LRP1 from microglia, but not from peripheral myeloid cells, exacerbates EAE progression. a LRP1 expression was determined by flow cytometry on microglia and BMDM isolated from LysMcre-Lrp1fl/fl and Lrp1fl/fl mice. b Clinical scores and c incidence of LysMcre-Lrp1fl/fl and Lrp1fl/fl mice (n = 7–9 for each group, representative of 3 independent experiments). d LRP1 expression was determined by flow cytometry on microglia and BMDM isolated from Cx3cr1creER-Lrp1fl/fl and Lrp1fl/fl mice. e Clinical scores and f incidence of Cx3cr1creER-Lrp1fl/fl and Lrp1fl/fl mice (n = 6–10 for each group, representative of 3 independent experiments.). 2-way ANOVA was used for the mean clinical score and the log-rank (Mantle-Cox) test was used for incidence. ***p < 0.001, mean ± s.e.m
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Fig2: Deletion of LRP1 from microglia, but not from peripheral myeloid cells, exacerbates EAE progression. a LRP1 expression was determined by flow cytometry on microglia and BMDM isolated from LysMcre-Lrp1fl/fl and Lrp1fl/fl mice. b Clinical scores and c incidence of LysMcre-Lrp1fl/fl and Lrp1fl/fl mice (n = 7–9 for each group, representative of 3 independent experiments). d LRP1 expression was determined by flow cytometry on microglia and BMDM isolated from Cx3cr1creER-Lrp1fl/fl and Lrp1fl/fl mice. e Clinical scores and f incidence of Cx3cr1creER-Lrp1fl/fl and Lrp1fl/fl mice (n = 6–10 for each group, representative of 3 independent experiments.). 2-way ANOVA was used for the mean clinical score and the log-rank (Mantle-Cox) test was used for incidence. ***p < 0.001, mean ± s.e.m

Mentions: Myeloid cells involved in MS pathology are from two different origins, the yolk sac derived CNS resident microglia [27] and the peripheral infiltrating macrophages. To explore the function of myeloid LRP1, we used the well-accepted animal model of MS, EAE, in two different mice strains lacking LRP1 either in peripheral myeloid cells or in microglia. To study the function of LRP1 in peripheral myeloid cells, we induced EAE in LRP1 deleted LysMcre-Lrp1fl/fl or the control Lrp1fl/fl mice with the myelin oligodendrocyte glycoprotein (MOG35-55) peptide and scored the mice daily. While LysM is highly expressed in peripheral myeloid inflammatory cells, LysM expression in microglia is variable [9, 28]. Using LysMcre-Lrp1fl/fl mice [29], we observed complete deletion of LRP1 in bone marrow derived macrophages (BMDM), while we observed little to no decrease in basal microglial LRP1 expression, as demonstrated by flow cytometry (Fig. 2a). Given that we have previously shown that macrophage LRP1 functions as an inhibitor of inflammation, we were surprised to find that deletion of LRP1 in peripheral myeloid cells in LysMcre-Lrp1fl/fl mice had no effect on the clinical score or incidence of EAE (Fig. 2b-c). Clinical scores were also similar when the amount of mycobacterium was increased to induce a stronger EAE disease course (Additional file 1: Figure S1) [30].Fig. 2


LRP1 expression in microglia is protective during CNS autoimmunity.

Chuang TY, Guo Y, Seki SM, Rosen AM, Johanson DM, Mandell JW, Lucchinetti CF, Gaultier A - Acta Neuropathol Commun (2016)

Deletion of LRP1 from microglia, but not from peripheral myeloid cells, exacerbates EAE progression. a LRP1 expression was determined by flow cytometry on microglia and BMDM isolated from LysMcre-Lrp1fl/fl and Lrp1fl/fl mice. b Clinical scores and c incidence of LysMcre-Lrp1fl/fl and Lrp1fl/fl mice (n = 7–9 for each group, representative of 3 independent experiments). d LRP1 expression was determined by flow cytometry on microglia and BMDM isolated from Cx3cr1creER-Lrp1fl/fl and Lrp1fl/fl mice. e Clinical scores and f incidence of Cx3cr1creER-Lrp1fl/fl and Lrp1fl/fl mice (n = 6–10 for each group, representative of 3 independent experiments.). 2-way ANOVA was used for the mean clinical score and the log-rank (Mantle-Cox) test was used for incidence. ***p < 0.001, mean ± s.e.m
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Fig2: Deletion of LRP1 from microglia, but not from peripheral myeloid cells, exacerbates EAE progression. a LRP1 expression was determined by flow cytometry on microglia and BMDM isolated from LysMcre-Lrp1fl/fl and Lrp1fl/fl mice. b Clinical scores and c incidence of LysMcre-Lrp1fl/fl and Lrp1fl/fl mice (n = 7–9 for each group, representative of 3 independent experiments). d LRP1 expression was determined by flow cytometry on microglia and BMDM isolated from Cx3cr1creER-Lrp1fl/fl and Lrp1fl/fl mice. e Clinical scores and f incidence of Cx3cr1creER-Lrp1fl/fl and Lrp1fl/fl mice (n = 6–10 for each group, representative of 3 independent experiments.). 2-way ANOVA was used for the mean clinical score and the log-rank (Mantle-Cox) test was used for incidence. ***p < 0.001, mean ± s.e.m
Mentions: Myeloid cells involved in MS pathology are from two different origins, the yolk sac derived CNS resident microglia [27] and the peripheral infiltrating macrophages. To explore the function of myeloid LRP1, we used the well-accepted animal model of MS, EAE, in two different mice strains lacking LRP1 either in peripheral myeloid cells or in microglia. To study the function of LRP1 in peripheral myeloid cells, we induced EAE in LRP1 deleted LysMcre-Lrp1fl/fl or the control Lrp1fl/fl mice with the myelin oligodendrocyte glycoprotein (MOG35-55) peptide and scored the mice daily. While LysM is highly expressed in peripheral myeloid inflammatory cells, LysM expression in microglia is variable [9, 28]. Using LysMcre-Lrp1fl/fl mice [29], we observed complete deletion of LRP1 in bone marrow derived macrophages (BMDM), while we observed little to no decrease in basal microglial LRP1 expression, as demonstrated by flow cytometry (Fig. 2a). Given that we have previously shown that macrophage LRP1 functions as an inhibitor of inflammation, we were surprised to find that deletion of LRP1 in peripheral myeloid cells in LysMcre-Lrp1fl/fl mice had no effect on the clinical score or incidence of EAE (Fig. 2b-c). Clinical scores were also similar when the amount of mycobacterium was increased to induce a stronger EAE disease course (Additional file 1: Figure S1) [30].Fig. 2

Bottom Line: While T cells are known orchestrators of the immune response leading to MS pathology, the precise contribution of CNS resident and peripheral infiltrating myeloid cells is less well described.We further show that the increased disease severity in experimental autoimmune encephalomyelitis is not due to haplodeficiency of the Cx3cr1 locus.At the cellular level, microglia lacking LRP1 adopt a pro-inflammatory phenotype characterized by amoeboid morphology and increased production of the inflammatory mediator TNF-α.

View Article: PubMed Central - PubMed

Affiliation: Center for Brain Immunology and Glia, Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.

ABSTRACT
Multiple sclerosis is a devastating neurological disorder characterized by the autoimmune destruction of the central nervous system myelin. While T cells are known orchestrators of the immune response leading to MS pathology, the precise contribution of CNS resident and peripheral infiltrating myeloid cells is less well described. Here, we explore the myeloid cell function of Low-density lipoprotein receptor-related protein-1 (LRP1), a scavenger receptor involved in myelin clearance and the inflammatory response, in the context of Multiple sclerosis. Supporting its central role in Multiple sclerosis pathology, we find that LRP1 expression is increased in Multiple sclerosis lesions in comparison to the surrounding healthy tissue. Using two genetic mouse models, we show that deletion of LRP1 in microglia, but not in peripheral macrophages, negatively impacts the progression of experimental autoimmune encephalomyelitis, an animal model of Multiple sclerosis. We further show that the increased disease severity in experimental autoimmune encephalomyelitis is not due to haplodeficiency of the Cx3cr1 locus. At the cellular level, microglia lacking LRP1 adopt a pro-inflammatory phenotype characterized by amoeboid morphology and increased production of the inflammatory mediator TNF-α. We also show that LRP1 functions as a robust inhibitor of NF-kB activation in myeloid cells via a MyD88 dependent pathway, potentially explaining the increase in disease severity observed in mice lacking LRP1 expression in microglia. Taken together, our data suggest that the function of LRP1 in microglia is to keep these cells in an anti-inflammatory and neuroprotective status during inflammatory insult, including experimental autoimmune encephalomyelitis and potentially in Multiple sclerosis.

No MeSH data available.


Related in: MedlinePlus