Csf1r, also known as Colony-Stimulating Factor-1 Receptor, is a receptor tyrosine kinase. It is crucial for controlling the differentiation and maintenance of most tissue-resident macrophages and bone-resorbing osteoclasts. Activation by endogenous cytokine ligation leads to autophosphorylation of its intracellular tyrosine kinase domain, triggering downstream pro-survival kinase cascades such as PI3K, ERK1/2, and JNK [1].

Genetic models have been insightful. For instance, deletion of the fms-intronic regulatory element (FIRE) in mice (a Csf1rΔFIRE/ΔFIRE model) selectively impacts Csf1r expression. These mice lack macrophages in the embryo, brain microglia, and resident macrophages in specific tissues like the skin, kidney, heart, and peritoneum, while the homeostasis of other macrophage populations and monocytes remains unaffected, except that monocytes and their progenitors in bone marrow lack surface Csf1r [4]. In a different context, conditional depletion of Csf1r in donor CX3CR1+ bone marrow-derived macrophages (BMDM) in graft-versus-host disease (GVHD) models showed that Csf1r inhibition exacerbated neuroinflammation and failed to reverse GVHD-induced behavioral changes [5].

In conclusion, Csf1r is essential for the development and function of specific macrophage populations. Gene-knockout and conditional-knockout mouse models have revealed its role in neurodegeneration-related leukoencephalopathy [2], cancer [1,3,6,7], and graft-versus-host disease [5]. Understanding Csf1r through these models provides valuable insights into related disease mechanisms and potential therapeutic strategies.

References:

1. Wen, Jiachen, Wang, Siyuan, Guo, Rongxian, Liu, Dan. 2022. CSF1R inhibitors are emerging immunotherapeutic drugs for cancer treatment. In European journal of medicinal chemistry, 245, 114884. doi:10.1016/j.ejmech.2022.114884. https://pubmed.ncbi.nlm.nih.gov/36335744/

2. Konno, Takuya, Kasanuki, Koji, Ikeuchi, Takeshi, Dickson, Dennis W, Wszolek, Zbigniew K. 2018. CSF1R-related leukoencephalopathy: A major player in primary microgliopathies. In Neurology, 91, 1092-1104. doi:10.1212/WNL.0000000000006642. https://pubmed.ncbi.nlm.nih.gov/30429277/

3. Cannarile, Michael A, Weisser, Martin, Jacob, Wolfgang, Ries, Carola H, Rüttinger, Dominik. 2017. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. In Journal for immunotherapy of cancer, 5, 53. doi:10.1186/s40425-017-0257-y. https://pubmed.ncbi.nlm.nih.gov/28716061/

4. Rojo, Rocío, Raper, Anna, Ozdemir, Derya D, Hume, David A, Pridans, Clare. 2019. Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations. In Nature communications, 10, 3215. doi:10.1038/s41467-019-11053-8. https://pubmed.ncbi.nlm.nih.gov/31324781/

5. Adams, Rachael C, Carter-Cusack, Dylan, Llanes, Genesis T, Zeiser, Robert, MacDonald, Kelli P A. . CSF1R inhibition promotes neuroinflammation and behavioral deficits during graft-versus-host disease in mice. In Blood, 143, 912-929. doi:10.1182/blood.2023022040. https://pubmed.ncbi.nlm.nih.gov/38048572/

6. Xun, Qiuju, Wang, Zhen, Hu, Xianglong, Ding, Ke, Lu, Xiaoyun. . Small-Molecule CSF1R Inhibitors as Anticancer Agents. In Current medicinal chemistry, 27, 3944-3966. doi:10.2174/1573394715666190618121649. https://pubmed.ncbi.nlm.nih.gov/31215373/

7. Lv, Qi, Zhang, Yishu, Gao, Wen, Hu, Lihong, Wang, Junwei. 2024. CSF1R inhibition reprograms tumor-associated macrophages to potentiate anti-PD-1 therapy efficacy against colorectal cancer. In Pharmacological research, 202, 107126. doi:10.1016/j.phrs.2024.107126. https://pubmed.ncbi.nlm.nih.gov/38432446/