Abstract
The impact of nanomaterials on immune cells is gaining attention but is not well documented. Here, we report a novel stimulating effect of carboxylated multi-walled carbon nanotubes (c-MWCNTs) on the migration of macrophages and uncover the underlying mechanisms, especially the upstream signaling, using a series of techniques including transwell migration assay, patch clamp, ELISA and confocal microscopy. c-MWCNTs dramatically stimulated the migration of RAW264.7 macrophages when endocytosed, and this effect was abolished by inhibiting phospholipase C (PLC) with U-73122, antagonizing the IP3 receptor with 2-APB, and blocking calcium release-activated calcium (CRAC) channels with SK&F96365. c-MWCNTs directly activated PLC and increased the IP3 level and [Ca2+]i level in RAW264.7 cells, promoted the translocation of the ER-resident stromal interaction molecule 1 (STIM1) towards the membranous calcium release-activated calcium channel modulator 1 (Orai1), and increased CRAC current densities in both RAW264.7 cells and HEK293 cells stably expressing the CRAC channel subunits Orai1 and STIM1. c-MWCNTs also induced dramatic spatial polarization of KCa3.1 channels in the RAW264.7 cells. We conclude that c-MWCNT is an activator of PLC and strongly recruits macrophages via the PLC/IP3/CRAC channel signaling cascade. These novel findings may provide a fundamental basis for the impact of MWCNTs on the immune system.
Highlights
Carbon nanotubes (CNTs), a one-dimensional nanomaterial with unusual mechanical, electrical and chemical properties, have applications in many fields such as material engineering, drug delivery[1,2,3], scaffolding for neuronal growth[4,5,6,7] and bone cell proliferation[8]
The present study focused on the impact and mechanism of c-multi-walled carbon nanotubes (MWCNTs) on macrophage migration
Based on the results of transwell assays, we found that c-MWCNTs act as a chemokine and strongly stimulate the migration of RAW264.7 macrophages
Summary
Carbon nanotubes (CNTs), a one-dimensional nanomaterial with unusual mechanical, electrical and chemical properties, have applications in many fields such as material engineering, drug delivery[1,2,3], scaffolding for neuronal growth[4,5,6,7] and bone cell proliferation[8]. M2 mixed status and stimulated macrophages to secrete a large amount of MIP-1α and MIP-2 to recruit macrophages and produce angiogenesis-related cytokines These findings depicted the downstream events of activated macrophages in response to MWCNT exposure. The calcium mobilization process in immune cells involves Ca2+ influx through certain Ca2+ channels such as the calcium release-activated calcium (CRAC) channel, and Ca2+ release from the endoplasmic reticulum (ER) via the Ca2+-releasing channel inositol 1,4,5-trisphosphate receptor (IP3R). We noticed in the early stage of the present study that exposure of RAW264.7 macrophages to c-MWCNTs leads to activation of CRAC channels and dramatic cell migration, and this finding inspired us to explore the action mechanisms of c-MWCNTs in recruiting macrophages
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