Differentiation of monocytes to macrophages with GM-CSF impairs ACOD1 and Itaconate production after TLR-4 activation.
Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B239
Abstract ID: 4212
Presenting Author:
Eduardo Patino-Martinez , Postdoc at NIH, NIAMS, NIH
Abstract:
Itaconate is a metabolite generated by the Krebs cycle enzyme Aconitate Decarboxylase 1 (ACOD1) and reported to have anti-inflammatory properties. GM-CSF is produced in inflammation, while M-CSF is produced under normal conditions. In vitro, the first one give rise to macrophages with a pro-inflammatory profile (GM-M𝝓) and the second one to cells resembling resident macrophages (M-M𝝓). Here, we evaluated the expression of ACOD1 in both types of macrophages after Lipopolysaccharide (LPS) activation. The results revealed that ACOD1 and itaconate are induced in both types of macrophages, but the induction is lower in GM-M𝝓 compared to M-M𝝓. Furthermore, we found that NFkB, MAPKs, and STING pathway activation is required for ACOD1 induction in GM-M𝝓, whereas in M-M𝝓, it is mainly mediated by MAPKs activation. Also, we found that ACOD1 protein expression in GM-M𝝓 is dependent on Histone acetyl-transferase II activity. Because previous works exploring the effect of 4- Octyl Itaconate (4-OI, an itaconate derivate) are made on M-M𝝓, we decided to compare the effect of 4-OI in GM-M𝝓 and M-M𝝓. We found that 4-OI increases basal respiration and ATP production in GM-M𝝓, but not in M-M𝝓. Importantly, 4-OI regulates the inflammatory response by decreasing TNF-𝛼 and IL-6 production exclusively in GM-M𝝓. These findings provide valuable insights into the regulation of ACOD1–itaconate and highlight the differential responses of GM-M𝝓 and M-M𝝓 to itaconate derivatives.
Differentiation of monocytes to macrophages with GM-CSF impairs ACOD1 and Itaconate production after TLR-4 activation.
Category
Poster and Podium (Block Symposium)