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HDAC6 deacetylase activity is critical for lipopolysaccharide-induced activation of macrophages.

Yan B, Xie S, Liu Z, Ran J, Li Y, Wang J, Yang Y, Zhou J, Li D, Liu M - PLoS ONE (2014)

Bottom Line: However, the molecular mechanisms of how macrophages are activated are not fully understood.Our data show that suppression of HDAC6 activity significantly restrains LPS-induced activation of macrophages and production of pro-inflammatory cytokines.Further study reveals that the regulation of macrophage activation by HDAC6 is independent of F-actin polymerization and filopodium formation; instead, it is mediated by the effects of HDAC6 on cell adhesion and microtubule acetylation.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.

ABSTRACT
Activated macrophages play an important role in both innate and adaptive immune responses, and aberrant activation of macrophages often leads to inflammatory and immune disorders. However, the molecular mechanisms of how macrophages are activated are not fully understood. In this study, we identify a novel role for histone deacetylse 6 (HDAC6) in lipopolysaccharide (LPS)-induced macrophage activation. Our data show that suppression of HDAC6 activity significantly restrains LPS-induced activation of macrophages and production of pro-inflammatory cytokines. Further study reveals that the regulation of macrophage activation by HDAC6 is independent of F-actin polymerization and filopodium formation; instead, it is mediated by the effects of HDAC6 on cell adhesion and microtubule acetylation. These data thus suggest that HDAC6 is an important regulator of LPS-induced macrophage activation and might be a potential target for the management of inflammatory disorders.

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Inhibition of HDAC6 enhances LPS-induced microtubule acetylation during macrophage activation.(A) RAW264.7 cells were treated with tubacin for 4 hours and stimulated with LPS for the indicated time. Acetylated α-tubulin and total α-tubulin were then analyzed by immunoblotting. (B) Experiments were performed as in panel A, and the level of tubulin acetylation was quantified and normalized to the 0-hour LPS stimulation of the control group. (C) RAW264.7 cells were treated with tubacin for 4 hours and stimulated with LPS for the indicated time. F-actin (red), acetylated α-tubulin (green), and nuclei (blue) were then stained, and images were captured with a laser scanning confocal microscope.
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pone-0110718-g005: Inhibition of HDAC6 enhances LPS-induced microtubule acetylation during macrophage activation.(A) RAW264.7 cells were treated with tubacin for 4 hours and stimulated with LPS for the indicated time. Acetylated α-tubulin and total α-tubulin were then analyzed by immunoblotting. (B) Experiments were performed as in panel A, and the level of tubulin acetylation was quantified and normalized to the 0-hour LPS stimulation of the control group. (C) RAW264.7 cells were treated with tubacin for 4 hours and stimulated with LPS for the indicated time. F-actin (red), acetylated α-tubulin (green), and nuclei (blue) were then stained, and images were captured with a laser scanning confocal microscope.

Mentions: We then investigated whether HDAC6 regulates LPS-stimulated macrophage activation by regulating microtubule dynamics. We first examined the level of acetylated microtubules in activated macrophages. As shown in the Fig. 5A and 5B, microtubule acetylation was remarkably elevated upon LPS stimulation, and tubacin significantly enhanced microtubule acetylation compared with the control group. By immunostaining, we found that in the control group, acetylated microtubules mainly concentrated on the microtubule organizing center at 0, 6, and 12 hours of LPS stimulation (Fig. 5C). With the time prolonging to 24 hours, macrophages became activated, accompanied with markedly increased microtubule acetylation (Fig. 5C, control). Consistent with the immunoblotting results, tubacin remarkably elevated microtubule acetylation (Fig. 5C), indicating that microtubule acetylation contributes to the role of HDAC6 in macrophage activation.


HDAC6 deacetylase activity is critical for lipopolysaccharide-induced activation of macrophages.

Yan B, Xie S, Liu Z, Ran J, Li Y, Wang J, Yang Y, Zhou J, Li D, Liu M - PLoS ONE (2014)

Inhibition of HDAC6 enhances LPS-induced microtubule acetylation during macrophage activation.(A) RAW264.7 cells were treated with tubacin for 4 hours and stimulated with LPS for the indicated time. Acetylated α-tubulin and total α-tubulin were then analyzed by immunoblotting. (B) Experiments were performed as in panel A, and the level of tubulin acetylation was quantified and normalized to the 0-hour LPS stimulation of the control group. (C) RAW264.7 cells were treated with tubacin for 4 hours and stimulated with LPS for the indicated time. F-actin (red), acetylated α-tubulin (green), and nuclei (blue) were then stained, and images were captured with a laser scanning confocal microscope.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4199742&req=5

pone-0110718-g005: Inhibition of HDAC6 enhances LPS-induced microtubule acetylation during macrophage activation.(A) RAW264.7 cells were treated with tubacin for 4 hours and stimulated with LPS for the indicated time. Acetylated α-tubulin and total α-tubulin were then analyzed by immunoblotting. (B) Experiments were performed as in panel A, and the level of tubulin acetylation was quantified and normalized to the 0-hour LPS stimulation of the control group. (C) RAW264.7 cells were treated with tubacin for 4 hours and stimulated with LPS for the indicated time. F-actin (red), acetylated α-tubulin (green), and nuclei (blue) were then stained, and images were captured with a laser scanning confocal microscope.
Mentions: We then investigated whether HDAC6 regulates LPS-stimulated macrophage activation by regulating microtubule dynamics. We first examined the level of acetylated microtubules in activated macrophages. As shown in the Fig. 5A and 5B, microtubule acetylation was remarkably elevated upon LPS stimulation, and tubacin significantly enhanced microtubule acetylation compared with the control group. By immunostaining, we found that in the control group, acetylated microtubules mainly concentrated on the microtubule organizing center at 0, 6, and 12 hours of LPS stimulation (Fig. 5C). With the time prolonging to 24 hours, macrophages became activated, accompanied with markedly increased microtubule acetylation (Fig. 5C, control). Consistent with the immunoblotting results, tubacin remarkably elevated microtubule acetylation (Fig. 5C), indicating that microtubule acetylation contributes to the role of HDAC6 in macrophage activation.

Bottom Line: However, the molecular mechanisms of how macrophages are activated are not fully understood.Our data show that suppression of HDAC6 activity significantly restrains LPS-induced activation of macrophages and production of pro-inflammatory cytokines.Further study reveals that the regulation of macrophage activation by HDAC6 is independent of F-actin polymerization and filopodium formation; instead, it is mediated by the effects of HDAC6 on cell adhesion and microtubule acetylation.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, China.

ABSTRACT
Activated macrophages play an important role in both innate and adaptive immune responses, and aberrant activation of macrophages often leads to inflammatory and immune disorders. However, the molecular mechanisms of how macrophages are activated are not fully understood. In this study, we identify a novel role for histone deacetylse 6 (HDAC6) in lipopolysaccharide (LPS)-induced macrophage activation. Our data show that suppression of HDAC6 activity significantly restrains LPS-induced activation of macrophages and production of pro-inflammatory cytokines. Further study reveals that the regulation of macrophage activation by HDAC6 is independent of F-actin polymerization and filopodium formation; instead, it is mediated by the effects of HDAC6 on cell adhesion and microtubule acetylation. These data thus suggest that HDAC6 is an important regulator of LPS-induced macrophage activation and might be a potential target for the management of inflammatory disorders.

Show MeSH
Related in: MedlinePlus