Abstract
Macrophages play critical roles in the onset of various diseases and in maintaining homeostasis. There are several functional subsets, of which M1 and M2 macrophages are of particular interest because they are differentially involved in inflammation and its resolution. Here, we investigated the differences in regulatory mechanisms between M1- and M2-polarized macrophages by examining mRNA metabolic machineries such as stress granules (SGs) and processing bodies (P-bodies). Human monocytic leukemia THP-1 cells cultured under M1-polarizing conditions (M1-THPs) had less ability to assemble oxidative-stress-induced SGs than those cultured under M2-polarizing conditions (M2-THPs). In contrast, P-body assembly in response to oxidative stress or TLR4 stimulation was increased in M1-THPs as compared to M2-THPs. These results suggest that mRNA metabolism is controlled differently in M1-THPs and M2-THPs. Interestingly, knocking down EDC4 or Dcp1a, which are components of P-bodies, severely reduced the production of IL-6, but not TNF-α in M1-THPs without decreasing the amount of IL-6 mRNA. This is the first report to demonstrate that the assembly of EDC4 and Dcp1a into P-bodies is critical in the posttranscriptional regulation of IL-6. Thus, improving our understanding of the mechanisms governing mRNA metabolism by examining macrophage subtypes may lead to new therapeutic targets.
Highlights
Macrophages play fundamental roles in inflammation and host defense, and in tissue remodeling and other homeostatic functions[1,2,3]
When M1-THPs and M2-THPs were treated with arsenite, we observed that T-cell intracellular antigen 1 (TIA1) and Ras-GAP SH3 domain binding protein 1 (G3BP1), which are essential components for assembling stress granules (SGs) [20], localized to cytoplasmic foci (Fig 1B)
A count of cytoplasmic dots stained with TIA1 and/or G3BP1 showed that M1-THPs had less ability than M2-THPs to form SGs (Fig 1C and 1D)
Summary
Macrophages play fundamental roles in inflammation and host defense, and in tissue remodeling and other homeostatic functions[1,2,3]. These cells exhibit phenotypic diversity and plasticity in response to various environmental factors, including cytokines and metabolites, and can change their activation phenotype to adapt to distinct environmental stimuli [2,4]. Alternative (M2) activation in the presence of IL-4 and IL-13 generates macrophages with anti-inflammatory properties that are associated with tissue remodeling and the resolution of inflammation[6,7]. Determining the precise nature of the unique regulatory mechanisms of polarized macrophages may lead to cell-type-specific therapeutic approaches that enhance host defense while preserving tissue integrity and preventing chronic inflammatory diseases
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