Oral Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

A neurodegenerative disease-causing colony stimulating factor 1 receptor (CSF1R) mutation alters tissue-resident macrophage population characteristics. (#36)

Jennifer S Stables 1 , Omkar Patkar 1 , Kim M Summers 1 , Katharine M Irvine 1 , David A Hume 1
  1. Mater Research Institute - UQ, Brisbane, Qld, Australia

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an early-onset neurodegenerative disease. It arises from heterozygous point mutations in Colony Stimulating Factor 1 Receptor (CSF1R).  CSF1R signalling is essential for macrophage differentiation, survival, and proliferation ALSP post-mortem samples demonstrate that microglia, tissue-resident macrophages of the brain, are reduced in number and morphologically altered. Little attention has been given to potential impacts on non-central nervous system macrophages, although patient monocytes display altered migration-related molecules. 

We created a novel mouse model harbouring a Csf1r mutation (a.a. E631K) found in ALSP patients. This model revealed that mutant receptors inhibit WT CSF1R signalling in heterozygous mice (Csf1rE631K/+). However, the cellular biology resulting in ALSP pathogenesis remains unclear. Tissues from Csf1rE631K/+ mice were compared to wild-type (Csf1+/+) littermates at 3, 7, 9, and 43 weeks of age.

Compared to wildtype, Csf1rE631K/+ mice had significantly fewer microglia at all ages. In 7- week-old mice, Csf1rE631K/+ microglia had a significantly larger cell body size and reduced branching length per cell. No significant difference in the number of doublecortin positive hippocampal newborn neurons was observed. However, Csf1rE631K/+ mice had significantly fewer hippocampal astrocytes. This indicates that altered microglial function may affect astrocyte biology in ALSP.

At 3 weeks of age, macrophages in Csf1rE631K/+ mice were either absent or greatly reduced in organs including the kidney, heart, skin, visceral adipose; and this was associated with a transient lag in postnatal growth in male Csf1rE631K/+ mice.  By 7 weeks of age, macrophages were present in most tissues in Csf1rE631K/+ mice, but morphologically resembled monocytes in some tissues (eg adipose), suggesting ongoing population of the niche in these mice.

In further characterising this novel model, we hope to reveal the underlying mechanisms by which ALSP occurs and gain further insight into the roles of CSF1R signalling in tissue homeostasis.