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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

Immune response and blood brain barrier permeability are not altered in microglial LRP1 deficient mice. Seven days after MOG immunization, draining lymph nodes were isolated from Cx3cr1creER-Lrp1fl/fl and Lrp1fl/fl mice and incubated with MOG. a-b IFN-γ and IL-17A production were determined by ELISA after 24 h. c BrdU incorporation by T cells was determined after 16 h by flow cytometry (n = 3–5 mice were used per group per experiment). Statistical analysis was performed with 2-way ANOVA. d The amount of fluorescein present in brains following LPS treatment (6 mg/kg) was measured in Cx3cr1creER-Lrp1fl/fl and Lrp1fl/fl mice to assess function of the blood brain barrier. Statistical analysis was performed with Student’s t-Test; means ± SEM
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Fig4: Immune response and blood brain barrier permeability are not altered in microglial LRP1 deficient mice. Seven days after MOG immunization, draining lymph nodes were isolated from Cx3cr1creER-Lrp1fl/fl and Lrp1fl/fl mice and incubated with MOG. a-b IFN-γ and IL-17A production were determined by ELISA after 24 h. c BrdU incorporation by T cells was determined after 16 h by flow cytometry (n = 3–5 mice were used per group per experiment). Statistical analysis was performed with 2-way ANOVA. d The amount of fluorescein present in brains following LPS treatment (6 mg/kg) was measured in Cx3cr1creER-Lrp1fl/fl and Lrp1fl/fl mice to assess function of the blood brain barrier. Statistical analysis was performed with Student’s t-Test; means ± SEM

Mentions: LRP1 is a multifunctional receptor with roles that could impact EAE progression at different levels [14]. As LRP1 functions in antigen presentation [32], and CX3CR1 may be expressed in subsets of antigen presenting cells (APC) in the periphery [33], we investigated the antigen recall response of inguinal lymph node T cells in the Cx3cr1creER-Lrp1fl/fl mice 7 days after immunization. Treatment with MOG35-55 peptide did not reveal any significant differences in T cell production of IFN-γ and IL-17A, as determined by ELISA (Fig. 4a-b). Furthermore, T cell proliferation measured by BrdU incorporation was also comparable to control cells (Fig. 4c). Taken together, these data suggest that increased disease severity in EAE for Cx3cr1creER-Lrp1fl/fl mice is not linked to impaired antigen presentation in the periphery.Fig. 4


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)

Immune response and blood brain barrier permeability are not altered in microglial LRP1 deficient mice. Seven days after MOG immunization, draining lymph nodes were isolated from Cx3cr1creER-Lrp1fl/fl and Lrp1fl/fl mice and incubated with MOG. a-b IFN-γ and IL-17A production were determined by ELISA after 24 h. c BrdU incorporation by T cells was determined after 16 h by flow cytometry (n = 3–5 mice were used per group per experiment). Statistical analysis was performed with 2-way ANOVA. d The amount of fluorescein present in brains following LPS treatment (6 mg/kg) was measured in Cx3cr1creER-Lrp1fl/fl and Lrp1fl/fl mice to assess function of the blood brain barrier. Statistical analysis was performed with Student’s t-Test; means ± SEM
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Related In: Results  -  Collection

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Fig4: Immune response and blood brain barrier permeability are not altered in microglial LRP1 deficient mice. Seven days after MOG immunization, draining lymph nodes were isolated from Cx3cr1creER-Lrp1fl/fl and Lrp1fl/fl mice and incubated with MOG. a-b IFN-γ and IL-17A production were determined by ELISA after 24 h. c BrdU incorporation by T cells was determined after 16 h by flow cytometry (n = 3–5 mice were used per group per experiment). Statistical analysis was performed with 2-way ANOVA. d The amount of fluorescein present in brains following LPS treatment (6 mg/kg) was measured in Cx3cr1creER-Lrp1fl/fl and Lrp1fl/fl mice to assess function of the blood brain barrier. Statistical analysis was performed with Student’s t-Test; means ± SEM
Mentions: LRP1 is a multifunctional receptor with roles that could impact EAE progression at different levels [14]. As LRP1 functions in antigen presentation [32], and CX3CR1 may be expressed in subsets of antigen presenting cells (APC) in the periphery [33], we investigated the antigen recall response of inguinal lymph node T cells in the Cx3cr1creER-Lrp1fl/fl mice 7 days after immunization. Treatment with MOG35-55 peptide did not reveal any significant differences in T cell production of IFN-γ and IL-17A, as determined by ELISA (Fig. 4a-b). Furthermore, T cell proliferation measured by BrdU incorporation was also comparable to control cells (Fig. 4c). Taken together, these data suggest that increased disease severity in EAE for Cx3cr1creER-Lrp1fl/fl mice is not linked to impaired antigen presentation in the periphery.Fig. 4

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