Progranulin loss dysregulates splenic and peripheral blood immune cells populations and may contribute to neuroinflammation and neurodegeneration in frontotemporal dementia (FTD)

Identification: Kukar, Thomas


Description

Progranulin loss dysregulates splenic and peripheral blood immune cells populations and may contribute to neuroinflammation and neurodegeneration in frontotemporal dementia (FTD)
 
Thomas L. Kukar1,3, Kathryn P. MacPherson2, George T. Kannarkat2, Elizabeth M. Kline2, Christopher Holler1,3, Georgia Taylor1,3, Danielle Oliver2, Valerie L. Joers2, Michelle A. Johnson1,2,3 and Malú G. Tansey2
1Department of Pharmacology, 2Department of Physiology, 3Department of Neurology Emory University, School of Medicine, Atlanta, Georgia 30322
 
Mutations in the progranulin gene (GRN) reduce circulating levels of progranulin (PGRN) and granulins (GRNs) and cause frontotemporal degeneration (FTD) the most common form of early-onset dementia. PGRN has been shown to be neuroprotective and to decrease amyloid β (Aβ) deposition in APP transgenic mice. Strategies to increase PGRN have been proposed to treat PGRN-deficient FTD and Alzheimer's disease (AD). Although expressed in neurons, PGRN is also highly expressed in microglia and other immune cells; but it is not known how PGRN loss in immune cells affects neuronal survival. Therefore, we focused on understanding how PGRN loss in microglia and all major subsets of peripheral immune cells may promote degeneration. Grn deficiency in mice is associated with marked increases in CD68+ myeloid cells, pro-inflammatory cytokine production, and circuit-specific synaptic pruning via complement activation. We performed immunohistological, proteomic, and deep-immunophenotyping analysis by flow cytometry on brain, spleen, and peripheral blood of Grn KO and WT mice ages 3-30 months. We found that in aged Grn KO mice microglia make up a smaller fraction of Cd11b+ Ly6G- cells and a large fraction of these microglia express higher levels of MHCII and lower levels of CD68 compared to WT mice. Further, the CD45 int CD11b hi population in the brain is increased in Grn KO mice relative to that in WT mice and a large fraction of them express MHCII and CD68 relative to WT mice, suggesting that peripheral immune cells have infiltrated the CNS. We also found a generalized increase in cell numbers in the blood with an increased frequency of T cells in Grn KO vs WT mice and decreased frequency of MHCII+ cells within Ly6C lo monocytes (alternative activation) and increased CD68 on Ly6C- monocytes. In addition, Grn KO mice displayed decreased NK and B cells, and macrophages in the spleen with decreased expression of MHC-II; and non-CD4/CD8 T-cells made up a larger proportion of CD3+ T cells. Proteomics and immunohistology also support the conclusion that peripheral immune cells infiltrated the CNS of Grn KO to a greater extent than in WT mice. These novel findings suggest that loss of PGRN leads to disruption of innate and adaptive immune responses. Analysis of peripheral immune cells may shed light on the role of PGRN in FTD and AD patients with GRN mutations or SNPs. Further, replacement of PGRN/GRNs may be a viable therapeutic strategy to treat PGRN-deficient FTD and AD.
 

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