Blockade of C5aR1 resets M1 via gut microbiota-mediated PFKM stabilization in a TLR5-dependent manner
Abstract Targeting C5aR1 modulates the function of infiltrated immune cells including tumor-associated macrophages (TAMs). The gut microbiome plays a pivotal role in colorectal cancer (CRC) tumorigenesis and development through TAM education. However, whether and how the gut flora is involved in C5a...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-06500-4 |
| _version_ | 1797273065699147776 |
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| author | Jie Zhao Chen Yao Yongqin Qin Hanyong Zhu Hui Guo Binbin Ji Xueqin Li Na Sun Rongqing Li Yuzhang Wu Kuiyang Zheng Yuchen Pan Tingting Zhao Jing Yang |
| author_facet | Jie Zhao Chen Yao Yongqin Qin Hanyong Zhu Hui Guo Binbin Ji Xueqin Li Na Sun Rongqing Li Yuzhang Wu Kuiyang Zheng Yuchen Pan Tingting Zhao Jing Yang |
| author_sort | Jie Zhao |
| collection | DOAJ |
| description | Abstract Targeting C5aR1 modulates the function of infiltrated immune cells including tumor-associated macrophages (TAMs). The gut microbiome plays a pivotal role in colorectal cancer (CRC) tumorigenesis and development through TAM education. However, whether and how the gut flora is involved in C5aR1 inhibition-mediated TAMs remains unclear. Therefore, in this study, genetic deletion of C5ar1 or pharmacological inhibition of C5aR1 with anti-C5aR1 Ab or PMX-53 in the presence or absence of deletion Abs were utilized to verify if and how C5aR1 inhibition regulated TAMs polarization via affecting gut microbiota composition. We found that the therapeutic effects of C5aR1 inhibition on CRC benefited from programming of TAMs toward M1 polarization via driving AKT2-mediated 6-phosphofructokinase muscle type (PFKM) stabilization in a TLR5-dependent manner. Of note, in the further study, we found that C5aR1 inhibition elevated the concentration of serum IL-22 and the mRNA levels of its downstream target genes encoded antimicrobial peptides (AMPs), leading to gut microbiota modulation and flagellin releasement, which contributed to M1 polarization. Our data revealed that high levels of C5aR1 in TAMs predicted poor prognosis. In summary, our study suggested that C5aR1 inhibition reduced CRC growth via resetting M1 by AKT2 activation-mediated PFKM stabilization in a TLR5-dependent manner, which relied on IL-22-regulated gut flora. |
| first_indexed | 2024-03-07T14:38:14Z |
| format | Article |
| id | doaj.art-d372a906775b4440b17e6178767adb6b |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-07T14:38:14Z |
| publishDate | 2024-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-d372a906775b4440b17e6178767adb6b2024-03-05T20:30:49ZengNature Publishing GroupCell Death and Disease2041-48892024-02-0115211210.1038/s41419-024-06500-4Blockade of C5aR1 resets M1 via gut microbiota-mediated PFKM stabilization in a TLR5-dependent mannerJie Zhao0Chen Yao1Yongqin Qin2Hanyong Zhu3Hui Guo4Binbin Ji5Xueqin Li6Na Sun7Rongqing Li8Yuzhang Wu9Kuiyang Zheng10Yuchen Pan11Tingting Zhao12Jing Yang13Jiangsu International Laboratory of Immunity and Metabolism, Jiangsu Province Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical UniversityJiangsu International Laboratory of Immunity and Metabolism, Jiangsu Province Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical UniversityJiangsu International Laboratory of Immunity and Metabolism, Jiangsu Province Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical UniversityJiangsu International Laboratory of Immunity and Metabolism, Jiangsu Province Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical UniversityJiangsu International Laboratory of Immunity and Metabolism, Jiangsu Province Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical UniversityJiangsu International Laboratory of Immunity and Metabolism, Jiangsu Province Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical UniversityJiangsu International Laboratory of Immunity and Metabolism, Jiangsu Province Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical UniversityJiangsu International Laboratory of Immunity and Metabolism, Jiangsu Province Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical UniversityJiangsu International Laboratory of Immunity and Metabolism, Jiangsu Province Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical UniversityChongqing International Institute for ImmunologyJiangsu International Laboratory of Immunity and Metabolism, Jiangsu Province Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical UniversityJiangsu International Laboratory of Immunity and Metabolism, Jiangsu Province Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical UniversityChongqing International Institute for ImmunologyJiangsu International Laboratory of Immunity and Metabolism, Jiangsu Province Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical UniversityAbstract Targeting C5aR1 modulates the function of infiltrated immune cells including tumor-associated macrophages (TAMs). The gut microbiome plays a pivotal role in colorectal cancer (CRC) tumorigenesis and development through TAM education. However, whether and how the gut flora is involved in C5aR1 inhibition-mediated TAMs remains unclear. Therefore, in this study, genetic deletion of C5ar1 or pharmacological inhibition of C5aR1 with anti-C5aR1 Ab or PMX-53 in the presence or absence of deletion Abs were utilized to verify if and how C5aR1 inhibition regulated TAMs polarization via affecting gut microbiota composition. We found that the therapeutic effects of C5aR1 inhibition on CRC benefited from programming of TAMs toward M1 polarization via driving AKT2-mediated 6-phosphofructokinase muscle type (PFKM) stabilization in a TLR5-dependent manner. Of note, in the further study, we found that C5aR1 inhibition elevated the concentration of serum IL-22 and the mRNA levels of its downstream target genes encoded antimicrobial peptides (AMPs), leading to gut microbiota modulation and flagellin releasement, which contributed to M1 polarization. Our data revealed that high levels of C5aR1 in TAMs predicted poor prognosis. In summary, our study suggested that C5aR1 inhibition reduced CRC growth via resetting M1 by AKT2 activation-mediated PFKM stabilization in a TLR5-dependent manner, which relied on IL-22-regulated gut flora.https://doi.org/10.1038/s41419-024-06500-4 |
| spellingShingle | Jie Zhao Chen Yao Yongqin Qin Hanyong Zhu Hui Guo Binbin Ji Xueqin Li Na Sun Rongqing Li Yuzhang Wu Kuiyang Zheng Yuchen Pan Tingting Zhao Jing Yang Blockade of C5aR1 resets M1 via gut microbiota-mediated PFKM stabilization in a TLR5-dependent manner Cell Death and Disease |
| title | Blockade of C5aR1 resets M1 via gut microbiota-mediated PFKM stabilization in a TLR5-dependent manner |
| title_full | Blockade of C5aR1 resets M1 via gut microbiota-mediated PFKM stabilization in a TLR5-dependent manner |
| title_fullStr | Blockade of C5aR1 resets M1 via gut microbiota-mediated PFKM stabilization in a TLR5-dependent manner |
| title_full_unstemmed | Blockade of C5aR1 resets M1 via gut microbiota-mediated PFKM stabilization in a TLR5-dependent manner |
| title_short | Blockade of C5aR1 resets M1 via gut microbiota-mediated PFKM stabilization in a TLR5-dependent manner |
| title_sort | blockade of c5ar1 resets m1 via gut microbiota mediated pfkm stabilization in a tlr5 dependent manner |
| url | https://doi.org/10.1038/s41419-024-06500-4 |
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