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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

LRP1 expression is increased in MS lesions. a Immunohistochemistry on consecutive sections from an early active (EA) MS lesion (upper row) shows: (1) myelin (PLP) laden macrophages consistent with ongoing demyelinating activity, (2) abundant macrophage infiltration (CD68), (3) hypertrophic reactive astrocytes indicating gliosis (GFAP), and (4) LRP1 immunoreactivity present on both astrocytes (arrowhead) and macrophages (arrow and inset). In contrast, the periplaque gray matter (PPGM, lower row) shows: (1) normal appearing myelin (PLP), (2) limited microglial reactivity (CD68), (3) astrocytes with regular size and morphology (GFAP), and (4) limited LRP1 immunoreactivity. (Scale bars = 20 μm). b Luxol Fast Blue histology (LFB) and immunofluorescence for CD68 and LRP1 shows that myeloid cells express LRP1 within the lesion (Scale bar = 100 μm)
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Fig1: LRP1 expression is increased in MS lesions. a Immunohistochemistry on consecutive sections from an early active (EA) MS lesion (upper row) shows: (1) myelin (PLP) laden macrophages consistent with ongoing demyelinating activity, (2) abundant macrophage infiltration (CD68), (3) hypertrophic reactive astrocytes indicating gliosis (GFAP), and (4) LRP1 immunoreactivity present on both astrocytes (arrowhead) and macrophages (arrow and inset). In contrast, the periplaque gray matter (PPGM, lower row) shows: (1) normal appearing myelin (PLP), (2) limited microglial reactivity (CD68), (3) astrocytes with regular size and morphology (GFAP), and (4) limited LRP1 immunoreactivity. (Scale bars = 20 μm). b Luxol Fast Blue histology (LFB) and immunofluorescence for CD68 and LRP1 shows that myeloid cells express LRP1 within the lesion (Scale bar = 100 μm)

Mentions: Our previous studies demonstrated that LRP1 functions as a receptor for myelin phagocytosis and a broad inhibitor of inflammation [11, 15], two key functions linked with MS pathogenesis. Because we observed increased expression of LRP1 in the CNS during an animal model of MS, experimental autoimmune encephalomyelitis (EAE) [11], we decided to probe the potential function of LRP1 during the human disease. We began by examining LRP1 expression in MS lesions at different stages of demyelinating activity. In the normal appearing periplaque gray matter, LRP1 was mainly detected in neurons (Fig. 1a, lower row), in agreement with a previous publication [26]. However, within the early active lesions, characterized by the presence of CD68+ myeloid cells containing myelin debris and GFAP+ reactive astrocytes, LRP1 expression was increased (Fig. 1a, upper row). Morphological analysis suggested that LRP1 expression was most prominent in myeloid cells (arrow) and astrocytes (arrowhead) in the early active lesion. The results from a total of 6 MS autopsies are summarized in Table 1. To confirm that myeloid cells express LRP1 within the active lesion, we performed double immunofluorescence with antibodies against LRP1 and CD68. Within the lesion, CD68+ cells are also LRP1+, while LRP1 is not detectable within the myeloid cells outside the lesion, confirming our immunohistochemistry results (Fig. 1b). LRP1 immunoreactivity in myeloid cells was also not present in inactive lesions (Table 1). Taken together, our results demonstrate that LRP1 expression in myeloid cells and astrocytes is increased during MS pathology.Fig. 1


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)

LRP1 expression is increased in MS lesions. a Immunohistochemistry on consecutive sections from an early active (EA) MS lesion (upper row) shows: (1) myelin (PLP) laden macrophages consistent with ongoing demyelinating activity, (2) abundant macrophage infiltration (CD68), (3) hypertrophic reactive astrocytes indicating gliosis (GFAP), and (4) LRP1 immunoreactivity present on both astrocytes (arrowhead) and macrophages (arrow and inset). In contrast, the periplaque gray matter (PPGM, lower row) shows: (1) normal appearing myelin (PLP), (2) limited microglial reactivity (CD68), (3) astrocytes with regular size and morphology (GFAP), and (4) limited LRP1 immunoreactivity. (Scale bars = 20 μm). b Luxol Fast Blue histology (LFB) and immunofluorescence for CD68 and LRP1 shows that myeloid cells express LRP1 within the lesion (Scale bar = 100 μm)
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Fig1: LRP1 expression is increased in MS lesions. a Immunohistochemistry on consecutive sections from an early active (EA) MS lesion (upper row) shows: (1) myelin (PLP) laden macrophages consistent with ongoing demyelinating activity, (2) abundant macrophage infiltration (CD68), (3) hypertrophic reactive astrocytes indicating gliosis (GFAP), and (4) LRP1 immunoreactivity present on both astrocytes (arrowhead) and macrophages (arrow and inset). In contrast, the periplaque gray matter (PPGM, lower row) shows: (1) normal appearing myelin (PLP), (2) limited microglial reactivity (CD68), (3) astrocytes with regular size and morphology (GFAP), and (4) limited LRP1 immunoreactivity. (Scale bars = 20 μm). b Luxol Fast Blue histology (LFB) and immunofluorescence for CD68 and LRP1 shows that myeloid cells express LRP1 within the lesion (Scale bar = 100 μm)
Mentions: Our previous studies demonstrated that LRP1 functions as a receptor for myelin phagocytosis and a broad inhibitor of inflammation [11, 15], two key functions linked with MS pathogenesis. Because we observed increased expression of LRP1 in the CNS during an animal model of MS, experimental autoimmune encephalomyelitis (EAE) [11], we decided to probe the potential function of LRP1 during the human disease. We began by examining LRP1 expression in MS lesions at different stages of demyelinating activity. In the normal appearing periplaque gray matter, LRP1 was mainly detected in neurons (Fig. 1a, lower row), in agreement with a previous publication [26]. However, within the early active lesions, characterized by the presence of CD68+ myeloid cells containing myelin debris and GFAP+ reactive astrocytes, LRP1 expression was increased (Fig. 1a, upper row). Morphological analysis suggested that LRP1 expression was most prominent in myeloid cells (arrow) and astrocytes (arrowhead) in the early active lesion. The results from a total of 6 MS autopsies are summarized in Table 1. To confirm that myeloid cells express LRP1 within the active lesion, we performed double immunofluorescence with antibodies against LRP1 and CD68. Within the lesion, CD68+ cells are also LRP1+, while LRP1 is not detectable within the myeloid cells outside the lesion, confirming our immunohistochemistry results (Fig. 1b). LRP1 immunoreactivity in myeloid cells was also not present in inactive lesions (Table 1). Taken together, our results demonstrate that LRP1 expression in myeloid cells and astrocytes is increased during MS pathology.Fig. 1

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