Requirement of Rab21 in LPS-induced TLR4 signaling and pro-inflammatory responses in macrophages and monocytes

• Published in: Biochemical and biophysical research communications Vol. 508; no. 1; pp. 169 - 176
• Main Authors: Li, Ping, Wu, Yong-hong, Zhu, Yan-ting, Li, Man-xiang, Pei, Hong-hong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2019
• Subjects: Adenoviridae; Cytokines; guanosinetriphosphatase; humans; inflammation; interleukin-1beta; interleukin-6; lipopolysaccharides; LPS; macrophages; mice; monocytes; Rab21; Signaling; TLR4; Toll-like receptor 4; transcription factor NF-kappa B; tumor necrosis factor-alpha; Signaling; Rab21; Cytokines; TLR4; LPS
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2018.11.074

Lipopolysaccharide (LPS) induces macrophage/monocyte activation and pro-inflammatory cytokines production by activating Toll-like receptor 4 (TLR-4) signaling. Rab GTPase 21 (Rab21) is a member of the Rab GTPase subfamily. In the present study, we show that LPS induced TLR4 and Rab21 association and endosomal translocation in murine bone marrow–derived macrophages (BMDMs) and primary human peripheral blood mononuclear cells (PBMCs). In BMDMs, shRNA-mediated stable knockdown of Rab21 inhibited LPS-induced expression and production of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α). Conversely, forced overexpression of Rab21 by an adenovirus construct potentiated LPS-induced IL-1β, IL-6 and TNF-α production in BMDMs. Further studies show that LPS-induced TLR4 endosomal traffic and downstream c-Jun and NFκB (nuclear factor-kappa B) activation were significantly inhibited by Rab21 shRNA, but intensified with Rab21 overexpression in BMDMs. Finally, in the primary human PBMCs, siRNA-induced knockdown of Rab21 significantly inhibited LPS-induced IL-1β, IL-6 and TNF-α production. Taken together, we suggest that Rab21 regulates LPS-induced pro-inflammatory responses by promoting TLR4 endosomal traffic and downstream signaling activation. •LPS induces TLR4 and Rab21 endosomal translocation.•LPS induces TLR4-Myd88-Rab21 association in macrophages and monocytes.•Rab21 shRNA inhibits LPS-induced pro-inflammatory cytokines production in BMDMs.•Rab21 overexpression facilitates LPS-induced pro-inflammatory cytokines production.•Rab21 regulates LPS-induced TLR4 endosomal traffic and downstream signaling activation.