C3a elicits unique migratory responses in immature low-density neutrophils
C3a elicits unique migratory responses in immature low-density neutrophils
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DOI：
10.1038/s41388-020-1169-8
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发表时间：
2020-02-04
期刊：
影响因子：
8
通讯作者：
Siegel, Peter M.
中科院分区：
文献类型：
--
作者：
Hsu, Brian E.;Roy, Joannie;Siegel, Peter M.
中性粒细胞代表免疫系统的第一道防线，并迅速招募到发炎组织中。在癌症相关炎症中，表型异质性已归因于这种细胞类型，其中嗜中性粒细胞可以根据细胞/微环境表现出抗转移或促转移功能。在这里，我们证明了促转移的未成熟低密度中性粒细胞（iLDN）更有效地积累在小鼠的肝脏转移病灶相比，抗转移的成熟高密度中性粒细胞（HDN）。转录组学分析揭示了相对于HDN，iLDN中迁移特征的富集。我们发现，条件培养基来源于肝转移性乳腺癌细胞，但不是肺转移性变异体，特异性诱导趋化性的iLDN，而不是HDN。趋化反应是由于相对于HDN，iLDN中C3 aR的表面表达增加。此外，我们检测到来自肝转移性乳腺癌细胞与肺转移性乳腺癌细胞的癌细胞衍生的C3 a分泌升高。用小分子抑制剂SB 290157干扰C3 a/C3 aR信号传导轴，或通过短发夹RNA降低肝转移性乳腺癌细胞分泌的C3 a水平，可以分别在体外和体内消除iLDN的趋化反应。总之，这些数据揭示了新的机制，通过该机制，iLDN响应于从肝侵袭性4 T1乳腺癌细胞分泌的肿瘤衍生的C3 a而优先在携带转移的肝组织中积累。
Neutrophils represent the immune system's first line of defense and are rapidly recruited into inflamed tissue. In cancer associated inflammation, phenotypic heterogeneity has been ascribed to this cell type, whereby neutrophils can manifest anti- or pro-metastatic functions depending on the cellular/micro-environmental context. Here, we demonstrate that pro-metastatic immature low-density neutrophils (iLDNs) more efficiently accumulate in the livers of mice bearing metastatic lesions compared with anti-metastatic mature high-density neutrophils (HDNs). Transcriptomic analyses reveal enrichment of a migration signature in iLDNs relative to HDNs. We find that conditioned media derived from liver-metastatic breast cancer cells, but not lung-metastatic variants, specifically induces chemotaxis of iLDNs and not HDNs. Chemotactic responses are due to increased surface expression of C3aR in iLDNs relative to HDNs. In addition, we detect elevated secretion of cancer-cell derived C3a from liver-metastatic versus lung-metastatic breast cancer cells. Perturbation of C3a/C3aR signaling axis with either a small molecule inhibitor, SB290157, or reducing the levels of secreted C3a from liver-metastatic breast cancer cells by short hairpin RNAs, can abrogate the chemotactic response of iLDNs both in vitro and in vivo, respectively. Together, these data reveal novel mechanisms through which iLDNs prefentially accumulate in liver tissue harboring metastases in response to tumor-derived C3a secreted from the liver-aggressive 4T1 breast cancer cells.