An Inactivating Mutation in Rat IL-34 Reveals Redundant and Nonredundant Functions of CSF1-IL-34 Signalling in Homeostasis and Inflammation

Colony stimulating factor 1 receptor (CSF1R) is required for the differentiation and maintenance of many mononuclear phagocyte lineage cells and is a definitive marker of this lineage in humans and mice. CSF1R signaling is activated by two cognate ligands CSF1 and IL34. In mice, the expression of CSF1 and IL34 is spatially regulated in homeostasis and increased in inflammatory conditions. Whereas CSF1 expression is ubiquitous, IL34 expression is predominantly observed in the epidermis and central nervous system. Accordingly, IL34-deficient mice lack Langerhan's cells and grey matter microglia. CSF1-deficient mice lack many tissue macrophage populations, but microglia and Langerhan's cells are present. In other species, including humans and rats, IL34 is more broadly expressed, raising the possibility that IL34 plays distinct roles, or that there is more redundancy between CSF1R ligands, in species other than mice. We generated and characterised a novel IL34 knockout rat. IL34 KO rats are phenotypically indistinguishable from wildtype littermates from birth up to 2 years of age. Similar to mice, grey matter microglia are significantly reduced in IL34-deficient animals in a dose dependent manner (+/+ > +/- > -/-). The loss of grey matter microglia was not associated with any observable histological pathology or behavioural abnormalities. IL34 KO rats also have a reduction in the number of Langerhan's cells, but do not completely lack them, unlike IL34 KO mice. Blood and bone marrow monocytes and all other tissue macrophage populations examined were indistinguishable between IL34 KO rats and littermate controls. To investigate the role of IL34 in tissue injury we utilised an adenine diet-induced chronic kidney disease (CKD) model, since Il34 is relatively highly expressed in the rat kidney. Both Il34 and Csf1 were induced in chronically injured kidneys. IL34 KO rats had reduced macrophage numbers in injured kidneys, but the KO did not affect pathology at peak injury or recovery after cessation of the adenine diet. We conclude that IL34 is largely redundant for the maintenance of monocyte-macrophage lineage cells and normal physiological homeostasis at steady state in rats.