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J. Biol. Chem., Vol. 278, Issue 50, 49911-49919, December 12, 2003

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Engulfment of Apoptotic Cells Is Negatively Regulated by Rho-mediated Signaling^*

Annie-Carole Tosello-Trampont, Kumiko Nakada-Tsukui, and Kodi S. Ravichandran

From the Beirne Carter Center for Immunology Research and the Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908

The rapid and efficient phagocytosis of apoptotic cells plays a critical role in preventing secondary necrosis, inflammation as well as in tissue remodeling and regulating immune responses. However, the molecular details of engulfment are just beginning to be elucidated. Among the Rho family GTPases, previous studies have implicated a role for Rac and Cdc42 in the uptake of apoptotic cells by phagocytes, yet the role of Rho has remained unclear. Here, we present evidence that Rho-GTP levels decrease during engulfment. RhoA seems to negatively affect basal engulfment, such that inhibition of Rho-mediated signaling in phagocytes enhanced the uptake of apoptotic targets. Activation of endogenous Rho or overexpression of constitutively active forms of Rho also inhibited engulfment. By testing mutants of RhoA that selectively activate downstream effectors, the Rho-kinase seemed to be primarily responsible for this inhibitory effect. Taken together, these data suggest that inhibition of Rho- and Rho-kinase-mediated signaling might be important during engulfment, which could have important implications for several clinical trials involving inhibition of the Rho kinase.

Received for publication, June 10, 2003 , and in revised form, September 23, 2003.

^* This work was supported in part by an RO1 grant from NIGMS of the National Institutes of Health (to K. S. R.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3.

To whom correspondence should be addressed: Carter Immunology Center, Bldg. MR4, Rm 4072D, Univ. of Virginia, Charlottesville, VA 22908. Tel.: 434-243-6093; Fax: 434-924-1221; E-mail: Ravi{at}virginia.edu.

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