Mutation in the rat interleukin 34 gene impacts macrophage development, homeostasis and inflammation in the brain and periphery

Interleukin-34 (IL34) and colony stimulating factor 1 (CSF1) signal through a shared receptor (CSF1R) to control macrophage survival, differentiation and function. Here we describe the impact of loss of function mutation in the rat Il34 gene. Il34-/- rats showed a partial reduction in macrophages within squamous epithelia (Langerhans-like cells) and in the testis. In the brain, microglia and brain-associated macrophages were selectively depleted in grey matter. A gradient of microglial density in Il34-/- cortex suggests that CSF1 can diffuse outwards from the corpus callosum. The reduced density of microglia was not associated with detectable neuropathology or behavioural alterations. In RNA-seq analysis of cortex, hippocampus and thalamus the only change is selective and uniform loss of the microglial signature. In the periphery, increased Il34 expression has been associated with epithelial injury. In the adenine diet model of renal interstitial fibrosis both Il34 and Csf1 were induced. The absence of IL34 led to a significant reduction in macrophage recruitment compared to controls, but pathology assessed histologically or by detection of damage-associated mRNA signature was unaffected. We suggest that IL34 and CSF1 provide redundant signals to sustain microglia and to direct macrophage recruitment and repair tissue injury in the periphery.