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. 2011 Jan;178(1):284-95.
doi: 10.1016/j.ajpath.2010.11.002. Epub 2010 Dec 23.

Progranulin is a chemoattractant for microglia and stimulates their endocytic activity

Fiona Pickford  1 , Jacob Marcus, Luiz Miguel Camargo, Qiurong Xiao, Danielle Graham, Jan-Rung Mo, Matthew Burkhardt, Vinayak Kulkarni, Jamie Crispino, Heike Hering, Michael Hutton
Affiliations

Progranulin is a chemoattractant for microglia and stimulates their endocytic activity

Fiona Pickford et al. Am J Pathol. 2011 Jan.

Abstract

Mutations resulting in progranulin haploinsufficiency cause disease in patients with a subset of frontotemporal lobar degeneration; however, the biological functions of progranulin in the brain remain unknown. To address this subject, the present study initially assessed changes in gene expression and cytokine secretion in rat primary cortical neurons treated with progranulin. Molecular pathways enriched in the progranulin gene set included cell adhesion and cell motility pathways and pathways involved in growth and development. Secretion of cytokines and several chemokines linked to chemoattraction but not inflammation were also increased from progranulin-treated primary neurons. Therefore, whether progranulin is involved in recruitment of immune cells in the brain was investigated. Localized lentiviral expression of progranulin in C57BL/6 mice resulted in an increase of Iba1-positive microglia around the injection site. Moreover, progranulin alone was sufficient to promote migration of primary mouse microglia in vitro. Primary microglia and C4B8 cells demonstrated more endocytosis of amyloid β1-42 when treated with progranulin. These data demonstrate that progranulin acts as a chemoattractant in the brain to recruit or activate microglia and can increase endocytosis of extracellular peptides such as amyloid β.

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Figures

Figure 1
Figure 1
Changes in cytokines secreted from progranulin-treated primary neurons. Levels of 90 cytokines in conditioned media from rat primary cortical neurons treated with 10 nmol/L of progranulin for 8 hours. Cytokines were measured using a biotin label–based rat antibody array. A: Heat map shows cytokine levels normalized to a control pool. B: Cytokines from progranulin-treated media that were significantly different from controls. Red; upregulated, green; downregulated.
Figure 2
Figure 2
Progranulin attracts microglia in the brain. A: Representative C57BL/6 cortical brain sections containing the PGRN (progranulin)-lenti or GFP-lenti injection site immunostained for progranulin or the microglial marker Iba1. Mice were sacrificed at 2, 7, or 14 days after injection. Scale bar = 200 μm. B: Quantification of the number of microglia surrounding the PGRN-lenti injection site normalized to the number of microglia surrounding the GFP-lenti injection site, expressed as a percentage increase. Each point represents the mean value from 3 to 4 sections analyzed per mouse (analysis of variance, P = 0.02; Dunnet post hoc test *P <0.05. C: Number of microglia recruited to the injection site correlated closely with progranulin staining intensity. Each data point was obtained from 1 brain section (green square, GFP-lenti injection; blue triangle, PGRN-lenti expression).
Figure 3
Figure 3
Progranulin promotes microglial migration in vitro. Histogram of number of primary mouse microglia that migrated across a Transwell membrane toward the chemoattractants progranulin (P) or 10% FBS in DMEM (D-10). Results are the mean of 3 separate experiments, expressed as a percentage of the positive control (10% FBS). *P < 0.05 compared with DMEM/DMEM (no chemoattractant gradient) calculated using the t test.
Figure 4
Figure 4
No difference is observed in microglial migration in progranulin-deficient mice with lesions created using PBS. A: Number of Iba1-positive microglia surrounding a PBS lesion in progranulin knockout (Grn−/−) and wild-type (Grn+/+) mice. B: Each point represents the mean of 3 to 5 sections analyzed per mouse. There was no significant difference between the groups (t test).
Figure 5
Figure 5
C4B8 cells and primary microglia endocytose more Aβ1-42 in response to progranulin treatment. A–F: C4B8 cells incubated with Hilyte 488–tagged Aβ1-42 and progranulin. Internalized Aβ was measured using flow cytometry on 488-fluorescence. A: Untreated cells. B: Cells incubated with 100 nmol/L of Hilyte 488–tagged Aβ1-42. C: Cells incubated with 100 nmol/L of Hilyte 488–tagged Aβ1-42 and 10 nmol/L of progranulin. D: Cells incubated with 100 nmol/L of Hilyte 488–tagged Aβ1-42 and 100 nmol/L of proganulin. E: Cells incubated with 100 nmol/L of Hilyte 488–tagged Aβ1-42 and 5 μmol/L of cytocholasin D. F: Mean fluorescence intensity of samples A–E: A, red; B, green; C, blue; D, brown; E, purple. G–N: Mouse primary microglia incubated with Hilyte 488–tagged Aβ1-42 and progranulin. G: Untreated microglia. H: Microglia incubated with 100 nmol/L of Hilyte 488–tagged Aβ1-42. I: Microglia incubated with 100 nmol/L of progranulin. J: Microglia incubated with 100 nmol/L of Hilyte 488–tagged Aβ1-42 and 10 nmol/L of progranulin. K: Microglia incubated with 100 nmol/L of Hilyte 488–tagged Aβ1-42 and 100 nmol/L of progranulin. L: Microglia incubated with 100 nmol/L of Hilyte 488–tagged Aβ1-42 and 100 nmol/L of insulin. M: Microglia incubated with 100 nmol/L of Hilyte 488–tagged Aβ1-42 and 100 nmol/L of brain-derived neutrotrophic factor. N: Microglia incubated with 100 nmol/L of Hilyte 488–tagged Aβ1-42 and 10 nmol/L of proganulin. Acidic compartments stained with LysoTracker Red. Images obtained at 60× magnification using a Zeiss confocal microscope.
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