Function of CSF1 and IL34 in Macrophage Homeostasis, Inflammation, and Cancer

Abstract

Colony-stimulating factor 1 (CSF1) and interleukin 34 (IL34) signal via the CSF1 receptor to regulate macrophage differentiation. Studies in IL34- or CSF1-deficient mice have revealed that IL34 function is limited to the central nervous system and skin during development. However, the roles of IL34 and CSF1 at homeostasis or in the context of inflammatory diseases or cancer in wild-type mice have not been clarified in vivo. By neutralizing CSF1 and/or IL34 in adult mice, we identified that they play important roles in macrophage differentiation, specifically in steady-state microglia, Langerhans cells, and kidney macrophages. In several inflammatory models, neutralization of both CSF1 and IL34 contributed to maximal disease protection. However, in a myeloid cell-rich tumor model, CSF1 but not IL34 was required for tumor-associated macrophage accumulation and immune homeostasis. Analysis of human inflammatory conditions reveals IL34 upregulation that may account for the protection requirement of IL34 blockade. Furthermore, evaluation of IL34 and CSF1 blockade treatment during Listeria infection reveals no substantial safety concerns. Thus, IL34 and CSF1 play non-redundant roles in macrophage differentiation, and therapeutic intervention targeting IL34 and/or CSF1 may provide an effective treatment in macrophage-driven immune-pathologies.

Inhibition of IL34 unveils tissue-selectivity and is sufficient to reduce microglial proliferation in chronic neurodegeneration

“…Similarly, a specific impact of IL-34 blockade on Langerhans cell homeostasis, but not on liver, intestine and kidney macrophages after IL-34 antibody administration has been recently shown 31 . We have also observed an effect on Langerhans cells, which were reduced after both CSF1R-and IL-34 antibody treatment, confirming a role of IL-34 in regulating their survival as well as the efficacy of anti-IL-34 antibodies.…”

“…The fact that blocking CSF1R using small molecule inhibitors resulted in pronounced depletion of microglia in several mouse models 5,7,8,10 , further indicates that the strategy applied in this study using blocking antibodies is not favourable. Lin et al and Easley-Neal et al, provide first proof that manipulation of IL-34 can be used to modify the microglia population in the gray matter of most brain regions 32 and that this approach might be relevant in the context of inflammatory diseases and cancer 31 . We extend these findings by showing that in a model of neurodegenerative disease, which is characterized by a pronounced expansion of the microglia population predominantly in the hippocampus, inhibition of IL-34 leads to reduced microglial proliferation.…”

Inhibition of IL-34 Unveils Tissue-Selectivity and Is Sufficient to Reduce Microglial Proliferation in a Model of Chronic Neurodegeneration

“…Long-term CSF1R inhibition could potentially increase risk of infections and lead to disturbance of tissue homeostasis due to the reduction of CSF1R-dependent macrophage populations in multiple organs. In a Listeria monocytogenes infection model, CSF-1/IL-34 blockade or treatment with anti-CSF-1 alone increased susceptibility to bacterial infection, although to a lower degree than anti-TNF therapy ( 32 ). Interestingly, IL-34 blockade did not alter infection susceptibility ( 32 ), indicating an immunosuppressive effect as observed with CSF-1 blockade can be prevented with anti-IL-34 treatment.…”

Drainage of inflammatory macromolecules from brain to periphery targets the liver for macrophage infiltration

“…The receptor tyrosine kinase CSF1R (also known as Fms) pathway regulates migration, differentiation, proliferation, and survival at varying degrees of different tissue-resident macrophages and monocytes in mammals and zebrafish [56,57]. Recent studies have implicated a role for this pathway in macrophage recruitment in disease, including the assembly of tumorassociated macrophages in various cancers [98][99][100][101][102]. Of particular interest IL-34 is elevated and implicated in the inflammation process of several inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease, and Sjogren's syndrome [103][104][105][106][107].…”