PT - JOURNAL ARTICLE AU - Huang, Han-Ying AU - Chen, Yan-Zhou AU - Zheng, Xin-Nan AU - Yue, Jia-Xing AU - Ju, Huai-Qiang AU - Shi, Yan-Xia AU - Tian, Lin TI - Availability of an inflammatory macrophage niche drives phenotypic and functional alterations in Kupffer cells AID - 10.1101/2024.04.23.590829 DP - 2024 Jan 01 TA - bioRxiv PG - 2024.04.23.590829 4099 - http://biorxiv.org/content/early/2024/04/28/2024.04.23.590829.short 4100 - http://biorxiv.org/content/early/2024/04/28/2024.04.23.590829.full AB - Inflammatory signals lead to recruitment of circulating monocytes and induce their differentiation into disease-associated macrophages1–3. Therefore, whether blocking inflammatory monocytes can mitigate disease progression is being actively evaluated4. Here, we employed multiple lineage tracing models and confirmed that monocyte-derived macrophages (mo-macs) are the major population of liver metastasis-associated macrophages (LMAMs), while the population of Kupffer cells (KCs), liver-resident macrophages, is diminished in liver metastatic nodules. Paradoxically, genetic ablation of mo-macs resulted in only a marginal decrease in LMAMs. Using a proliferation recording system and a KC tracing model in a monocyte-deficient background, we found that LMAMs can be replenished either via increased local macrophage proliferation or by promoting KC infiltration. After occupying macrophage niches left vacant by monocyte depletion, KCs exhibit substantial phenotypic and functional alterations through epigenetic reprogramming. These data suggest that dual blockade of monocytes and macrophages could be used to effectively target immunosuppressive myelopoiesis and to reprogram the microenvironment towards an immunostimulatory state.Competing Interest StatementThe authors have declared no competing interest.