School of Medicine Publications and Presentations
205-LB: ERK Is Required for LPS-Induced TLR4 Internalization in Macrophages
Document Type
Abstract
Publication Date
6-2022
Abstract
Insulin resistance is associated with circulating levels of lipopolysaccharide (LPS) released from the gut. Animal and human studies demonstrate that obesity increases gut permeability leading to elevated plasma LPS levels resulting in inflammation and metabolic dysfunction. Binding of LPS to Toll like receptor 4 (TLR4) leads to the internalization and trafficking of TLR4, inducing activation of downstream signaling pathways. TLR4 internalization in macrophages leads to activation of pro-inflammatory signaling pathways and production of factors linked to the development of insulin resistance. The extracellular signal-regulated kinase 1 and 2 (ERK1 and 2) are activated downstream of TLR4 and this activation is associated with insulin resistance. We hypothesized that ERK1 and ERK2 regulate TLR4 internalization in macrophages that are exposed to LPS. We examined whether inhibition of ERK activity blocks LPS-mediated internalization of TLR4 in bone marrow derived macrophages (BMDM) .We used siRNA to knockdown ERK1, ERK2, or both. BMDM were treated with LPS (100 ng/ml, 6hr) . Loss of cell surface TLR4 expression was measured by flow cytometry as a readout for TLR4 internalization. LPS decreased TLR4 surface expression by 31.3%, but knockdown of ERK1, ERK2, or both prevented LPS-induced decrease of TLR4 surface expression (5.6%, no decrease, 0.9%, respectively) . In addition, knockdown of either ERK1, ERK2, or both in RAW264.7 cells prevented LPS-induced activity of Rab5, the early endosomal protein associated with TLR4 translocation.
In summary, ERK regulates TLR4 endocytosis and trafficking in macrophages. We propose that ERK positively regulates LPS-mediated TLR4 internalization and inhibition of ERK signaling will protect against insulin resistance.
Recommended Citation
Chang, P. F., & Reyna, S. M. (2022). 205-LB: ERK Is Required for LPS-Induced TLR4 Internalization in Macrophages. Diabetes 1 June 2022; 71 (Supplement_1): 205–LB. https://doi.org/10.2337/db22-205-LB
Publication Title
Diabetes
DOI
10.2337/db22-205-LB
Academic Level
faculty
Mentor/PI Department
Office of Human Genetics
Comments
© 2022 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.