Alternations in inflammatory macrophage niche drive phenotypic and functional plasticity of Kupffer cells

Han-Ying Huang, Yan-Zhou Chen, Chuang Zhao, Xin-Nan Zheng, Kai Yu, Jia-Xing Yue, Huai-Qiang Ju, Yan-Xia Shi and Lin Tian ()
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Han-Ying Huang: Sun Yat-sen University Cancer Center
Yan-Zhou Chen: Sun Yat-sen University Cancer Center
Chuang Zhao: Sun Yat-sen University Cancer Center
Xin-Nan Zheng: Sun Yat-sen University Cancer Center
Kai Yu: The University of Texas MD Anderson Cancer Center
Jia-Xing Yue: Sun Yat-sen University Cancer Center
Huai-Qiang Ju: Sun Yat-sen University Cancer Center
Yan-Xia Shi: Sun Yat-sen University Cancer Center
Lin Tian: Sun Yat-sen University Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Inflammatory signals lead to recruitment of circulating monocytes and induce their differentiation into pro-inflammatory macrophages. Therefore, whether blocking inflammatory monocytes can mitigate disease progression is being actively evaluated. Here, we employ multiple lineage-tracing models and show that monocyte-derived macrophages (mo-mac) are the major population of immunosuppressive, liver metastasis-associated macrophages (LMAM), while the proportion of Kupffer cells (KC) as liver-resident macrophages is diminished in metastatic nodules. Paradoxically, genetic ablation of mo-macs results in only a marginal decrease in LMAMs. Using a proliferation-recording system and a KC-tracing model in a monocyte-deficient background, we find that LMAMs can be replenished either via increased local macrophage proliferation or by promoting KC infiltration. In the latter regard, KCs undergo transient proliferation and exhibit substantial phenotypic and functional alterations through epigenetic reprogramming following the vacating of macrophage niches by monocyte depletion. Our data thus suggest that a simultaneous blockade of monocyte recruitment and macrophage proliferation may effectively target immunosuppressive myelopoiesis and reprogram the microenvironment towards an immunostimulatory state.

Date: 2024
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DOI: 10.1038/s41467-024-53659-7

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