The iNOS/Src/FAK axis is critical in Toll-like receptor-mediated cell motility in macrophages

Ming Chei Maa, Miao Ying Chang, Jiarung Li, Yu Yun Li, Ming Yu Hsieh, Ching Jau Yang, Yen Jen Chen, Yahan Li, Hui Chen Chen, Wei Erh Cheng, Ching Yun Hsieh, Chun Wen Cheng, Tzeng Horng Leu

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Abstract

The Toll-like receptors (TLRs) play a pivotal role in innate immunity for the detection of highly conserved, pathogen-expressed molecules. Previously, we demonstrated that lipopolysaccharide (LPS, TLR4 ligand)-increased macrophage motility required the participation of Src and FAK, which was inducible nitric oxide synthase (iNOS)-dependent. To investigate whether this iNOS/Src/FAK pathway is a general mechanism for macrophages to mobilize in response to engagement of TLRs other than TLR4, peptidoglycan (PGN, TLR2 ligand), polyinosinic-polycytidylic acid (polyI:C, TLR3 ligand) and CpG-oligodeoxynucleotides (CpG, TLR9 ligand) were used to treat macrophages in this study. Like LPS stimulation, simultaneous increase of cell motility and Src (but not Fgr, Hck, and Lyn) was detected in RAW264.7, peritoneal macrophages, and bone marrow-derived macrophages exposed to PGN, polyI:C and CpG. Attenuation of Src suppressed PGN-, polyI:C-, and CpG-elicited movement and the level of FAK Pi-Tyr861, which could be reversed by the reintroduction of siRNA-resistant Src. Besides, knockdown of FAK reduced the mobility of macrophages stimulated with anyone of these TLR ligands. Remarkably, PGN-, polyI:C-, and CpG-induced Src expression, FAK Pi-Tyr861, and cell mobility were inhibited in macrophages devoid of iNOS, indicating the importance of iNOS. These findings corroborate that iNOS/Src/FAK axis occupies a central role in macrophage locomotion in response to engagement of TLRs.

Original languageEnglish
Pages (from-to)136-147
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1813
Issue number1
DOIs
Publication statusPublished - 2011 Jan 1

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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    Maa, M. C., Chang, M. Y., Li, J., Li, Y. Y., Hsieh, M. Y., Yang, C. J., Chen, Y. J., Li, Y., Chen, H. C., Cheng, W. E., Hsieh, C. Y., Cheng, C. W., & Leu, T. H. (2011). The iNOS/Src/FAK axis is critical in Toll-like receptor-mediated cell motility in macrophages. Biochimica et Biophysica Acta - Molecular Cell Research, 1813(1), 136-147. https://doi.org/10.1016/j.bbamcr.2010.09.004