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Human Macrophages Constitute Targets for Immunotoxic Inorganic Arsenic¹

Anthony Lemarie^*, Claudie Morzadec^*, Emilie Bourdonnay^*, Olivier Fardel^*, and Laurent Vernhet^2,*

^* Institut National de la Santé et de la Recherche Médicale, Unité 620, Détoxication et Réparation Tissulaire, Université de Rennes-1, and Département Hématologie, Immunologie et Therapie cellulaire, Centre Hospitalier Universitaire Pontchaillou, Rennes, France

Chronic exposure to inorganic arsenic, a widely distributed environmental contaminant, can lead to toxic effects, including immunosuppression. Owing to the established roles of human macrophages in immune defense, we determined, in the present study, whether inorganic arsenic can affect these major immune cells. Our results demonstrate that noncytotoxic concentrations of arsenic trioxide (As₂O₃), an inorganic trivalent form, markedly impair differentiated features of human blood monocyte-derived macrophages. First, treatment of macrophages with 1 µM As₂O₃ induced a rapid cell rounding and a subsequent loss of adhesion. These morphologic alterations were associated with a marked reorganization of actin cytoskeleton, which includes retraction of peripheral actin extensions and formation of a cortical actin ring. In addition, As₂O₃ reduced expression of various macrophagic surface markers, enhanced that of the monocytic marker CD14, and altered both endocytosis and phagocytosis; unexpectedly, exposure of macrophages to the metalloid also strongly potentiated expression of TNF and IL-8 induced by LPS. Finally, like monocytes, As₂O₃-treated macrophages can be differentiated into dendritic-like cells. Impairment of macrophage function by As₂O₃ mainly resulted from activation of a RhoA/Rho-associated kinase pathway; indeed, pretreatment of macrophages with the Rho-associated kinase inhibitor Y-27632 prevented metalloid effects on cytoskeleton and phagocytosis. Moreover, As₂O₃ was found to increase level of the active GTP-bound form of RhoA and that of phosphorylated-Moesin, a major cytoskeleton adaptor protein involved in RhoA regulation. Taken together, our results demonstrated that human macrophages constitute sensitive targets of inorganic arsenic, which may contribute to immunotoxicity of this environmental contaminant.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Association pour la Recherche sur le Cancer and Ligue Contre le Cancer (Comité d’Ille-et-Vilaine). A.L. and E.B. are recipients of a fellowship from Ligue Nationale Contre le Cancer and Ligue Contre le Cancer (Comité d’Ille-et-Vilaine), respectively.

² Address correspondence and reprint requests to Dr. Laurent Vernhet, Institut National de la Santé et de la Recherche Médicale, Unité 620, Faculté des Sciences Pharmaceutiques et Biologiques, Institut Fédératif de Recherche 140, Université de Rennes-1, 2 avenue du Professeur Léon Bernard, 35043 Rennes, France. E-mail address: Laurent.Vernhet{at}rennes.inserm.fr

³ Abbreviations used in this paper: iAs, inorganic arsenic; ERM, Ezrin/Radixin/Moesin; RhoGDI, Rho guanine dissociation inhibitor; A5, annexin V; SG, sytox green; MFI, mean fluorescence intensity; RT-qPCR, reverse transcription-real-time quantitative PCR; ROCK, Rho-associated kinase.

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The JI 2006 177: 2737-2738. [Full Text]  

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