Role And Mechanism Of CXCL10 In Inducing Alveolar Macrophages To Construct Premetastatic Niche

Primary tumors can promote the distant metastasis of tumors by driving the formation of the premetastatic niche in target organs.Nowadays,many studies have reported the role of bone marrow-derived cells,such as myeloid-derived suppressor cells(MDSCs)and tumor-associated neutrophils in the construction of the premetastatic niche,while the role and mechanism of tissue-resident cells remain unclear.A variety of tumors can specifically metastasize to the lung.It is known that macrophages in the lung can affect the adhesion,extravasation and early colonization of tumor cells.Moreover,macrophages are potential therapeutic targets in the secondary tumor microenvironment.In lung tissue,there are two types of macrophages,namely alveolar macrophages(AMs)and interstitial macrophages(IMs).Up to now,there have been many studies reported that IMs can promote tumor metastasis by helping tumor cell extravasation,survival and growth.However,the specific role of AMs,as tissue-resident macrophages,in promoting the formation of the premetastatic niche under tumor conditions and how they are induced and activated under tumor conditions to drive the construction of the premetastatic niche still remains unclear and require further study.We found that 1)AMs under tumor conditions can be activated to recruit monocytic MDSCs(mo-MDSCs)through increasing the expression of CCL12 to construct a premetastatic niche and promote tumor metastasis.2)Cytokine microarray experiments showed that the levels of IL-1β,CXCL10,CXCL1,CCL2,CCL12 and CXCL2 in the premetastatic lung of tumor-bearing mice increased significantly.Further experiments confirmed that CXCL10 can directly act on AMs and upregulate CCL12 expression and promotes the recruitment of mo-MDSCs.3)Through CXCR3 or TLR4,CXCL10 activates TAK1-NF-κB/ERK/JNK signaling pathways to induce the activation of AMs.The loss of CXCR3 or TLR4 receptor,and the use of CXCR3 or TLR4 receptor inhibitors can significantly reduce the expression of CCL12 in AMs,the recruitment of mo-MDSCs in the premetastatic niche and tumor metastasis.4)By transcriptome sequencing of AMs of tumor-bearing mice in the formation of the premetastatic niche at different stages,we found that UBE2 O expression was downregulated,and the downregulation of UBE2 O could significantly enhance the CCL12 expression of AMs induced by CXCL10.5)Mass spectrometry showed that UBE2 O can combine with TRAF6 and DDX3 X,and downregulation of UBE2 O in AMs regulates the activation of the TAK1-NF-κB/ERK/JNK signaling pathway by promoting the ubiquitination of TRAF6 or inhibiting the degradation of DDX3 X,and enhances the expression of CCL12 in AMs.These results indicate that increased CXCL10 in the premetastatic niche can induce the expression of CCL12 in AMs under tumor conditions,and then recruit mo-MDSCs to construct the premetastatic niche.At the same time,our study revealed the CXCL10,AMs surface receptors,receptor-mediated related signaling pathways,and the mechanism by which downregulation of UBE2 O in AMs under tumor conditions enhances CXCL10-induced CCL12 expression in AMs.In summary,our study explored how primary tumors induce AMs in the premetastatic niche to activate and promote the formation of premetastatic niche and revealed a mechanism by which AMs were activated.The clarification of the relevant content of this study was provided new evidence for the in-depth understanding of the mechanism of primary tumors inducing cells in distant target organs to promote the formation of the premetastatic niche.And we have also provided essential references for the design of anti-tumor drugs and clinical molecular diagnosis and treatment of targeted therapy for malignant tumors.