ORIGINAL ARTICLE

Cell Research (2008): 1-11
© 2008 IBCB, SIBS, CAS All rights reserved 1001-0602/06 $ 30.00
www.nature.com/cr

MyD88-independent activation of a novel actin-Cdc42/Rac pathway is required for Toll-like receptor-stimulated phagocytosis

Ling Kong^1,2 and Bao-Xue Ge¹

Correspondence: Bao-Xue Ge Tel/Fax: +86-21-63852784 E-mail: gebaoxue@sibs.ac.cn

Download as printable (PDF) file Full Text (html)file Search Medline for articles by: Ling Kong

Phagocytosis and subsequent degradation of pathogens by macrophages play a pivotal role in host innate immune responses to microbial infection. Recent studies have shown that Toll-like receptors (TLRs) play an important role in promoting the clearance of bacteria by up-regulating the phagocytic activity of macrophages. However, information regarding the signaling mechanism of TLR-mediated phagocytosis is still limited. Here, we provide evidence that the stimulation of TLR4 with LPS leads to activation of multiple signaling pathways including MAP kinases, phosphatidylinositide 3-kinase (PI3K), and small GTPases in the murine macrophage-like cell line RAW264.7. Specific inhibition of Cdc42/Rac or p38 MAP kinase, but not PI3K, reduced TLR4-induced phagocytosis of bacteria. Moreover, we have found that either inhibition of actin polymerization by cytochalasin D or the knockdown of actin by RNAi markedly reduced the activation of Cdc42 and Rac by LPS. TLR4-induced activation of Cdc42 and Rac appears to be independent of MyD88. Taken together, our results described a novel actin-Cdc42/Rac pathway through which TLRs can specifically provoke phagocytosis.

Cell Research advance online publication 10 June 2008; doi: 10.1038/cr.2008.65

Keywords: innate immunity, Toll-like receptors, phagocytosis, GTPases, actin, p38