Frontline Science: Kindlin-3 is essential for patrolling and phagocytosis functions of nonclassical monocytes during metastatic cancer surveillance

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

article

Paola M. Marcovecchio¹  Yanfang Peipei Zhu²  Richard N. Hanna¹  Huy Q. Dinh²  Robert Tacke³  Runpei Wu²  Sara McArdle²  Sophia Reynolds²  Daniel J. Araujo²  Klaus Ley⁴  Catherine C. Hedrick² 

[1] Department of Medicine, University of California San Diego School of Medicine;Center for Cancer Immunotherapy, La Jolla Institute for Immunology;COI Pharmaceuticals;Center for Autoimmunity and Inflammation, La Jolla Institute for Immunology

关键词: endothelium;    integrins;    lungs;    metastasis;    nonclassical monocytes;    patrolling;   

DOI  :  10.1002/JLB.4HI0420-098R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Nonclassical monocytes maintain vascular homeostasis by patrolling the vascular endothelium, responding to inflammatory signals, and scavenging cellular debris. Nonclassical monocytes also prevent metastatic tumor cells from seeding new tissues, but whether the patrolling function of nonclassical monocytes is required for this process is unknown. To answer this question, we utilized an inducible-knockout mouse that exhibits loss of the integrin-adaptor protein Kindlin3 specifically in nonclassical monocytes. We show that Kindlin-3-deficient nonclassical monocytes are unable to patrol the vascular endothelium in either the lungs or periphery. We also find that Kindlin-3-deficient nonclassical monocytes cannot firmly adhere to, and instead “slip” along, the vascular endothelium. Loss of patrolling activity by nonclassical monocytes was phenocopied by ablation of LFA-1, an integrin-binding partner of Kindlin-3. When B16F10 murine melanoma tumor cells were introduced into Kindlin-3-deficient mice, nonclassical monocytes showed defective patrolling towards tumor cells and failure to ingest tumor particles in vivo. Consequently, we observed a significant, 4-fold increase in lung tumor metastases in mice possessing Kindlin-3- deficient nonclassical monocytes. Thus, we conclude that the patrolling function of nonclassical monocytes is mediated by Kindlin-3 and essential for these cells to maintain vascular endothelial homeostasis and prevent tumor metastasis to the lung.

【 授权许可】

CC BY