Nitric oxide causes macrophage migration via the HIF-1-stimulated small GTPases Cdc42 and Rac1.
Hypoxia-inducible factor 1 (HIF-1) is a key regulator of tumor development. Recently, the tumor microenvironment, with the presence of tumor-associated macrophages (TAMs), has gained considerable interest. The mechanisms of macrophage/TAM migration as well as the role of HIF-1 in macrophages for tumor progression are still under debate. We present evidence that under normoxic conditions, nitric oxide (NO) promotes macrophage migration. The response was impaired in macrophages from leukocyte conditional HIF-1 alpha(-/-) mice. NO production and cell migration in response to cytokines were attenuated in macrophages from iNOS(-/-) mice, suggesting that iNOS-derived NO transmits cytokine signaling toward cell migration. We further identified the small GTPases Cdc42 and Rac1 as effectors of the NO-HIF axis to drive macrophage migration by modulating the actin cytoskeleton. Our observations strengthen the role of HIF-1 in macrophages as a target of NO in facilitating functional responses such as migration.
Zhou
Jie
J
Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany.
Dehne
Nathalie
N
Brüne
Bernhard
B
D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D003599:Cytoskeleton / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein