Distinct role of FoxO1 in M-CSF- and GM-CSF-differentiated macrophages contributes LPS-mediated IL-10: implication in hyperglycemia

Abstract

Macrophages are a heterogeneous population of immune cells that are essential for the initiation and containment inflammation. There are 2 well-established populations of inflammatory macrophages: classically activated M1 and alternatively activated M2 macrophages. The FoxO family of transcription factors plays key roles in a number of cellular processes, including cell growth, metabolism, survival, and inflammation. In this study, we determined whether the expression of FoxO1 contributes polarization of macrophages toward the M2-like phenotype by enhancing IL-10 cytokine expression. We identified that FoxO1 is highly expressed in M-CSF-derived (M2-like) macrophage subsets, and this M2-like macrophages showed a preferential FoxO1 enrichment on the IL-10 promoter but not in GM-CSF-derived (M1-like) macrophages during classic activation by LPS treatment, which suggests that FoxO1 enhances IL-10 by binding directly to the IL-10 promoter, especially in BMMs. In addition, our data show that macrophages in the setting of hyperglycemia contribute to the macrophage-inflammatory phenotype through attenuation of the contribution of FoxO1 to activate IL-10 expression. Our data identify a novel role for FoxO1 in regulating IL-10 secretion during classic activation and highlight the potential for therapeutic interventions for chronic inflammatory conditions, such as atherosclerosis, diabetes, inflammatory bowel disease, and arthritis.

小鼠脾脏、腹腔和骨髓源性巨噬细胞特征比较

“…We found that BMs were partially polarized to M2 based on flow cytometry and PCR, suggesting that M-CSF polarized macrophages generate an increased number of anti-inflammatory factors. Granulocyte-macrophage (GM)-CSF induces macrophages to produce higher amounts of inflammatory factors (Chung et al, 2015).…”

GM-CSF Grown Bone Marrow Derived Cells Are Composed of Phenotypically Different Dendritic Cells and Macrophages

“…In fact, these GM-CSF grown macrophages could produce even more extensive proinflammatory cytokines compared to M-CSF grown, INFγ/LPS polarized macrophages (preliminary data). Despite the remarkable inflammatory phenotype of GM-CSF grown macrophages, there is much confusion about the use of these cells because they have been used as both macrophages and DCs without any guiding criteria (Bhattacharya et al, 2011; Chung et al, 2015; Ganesh et al, 2009). Consequently, we sought to distinguish amongst the heterogenous populations of GM-CSF derived cells and especially focused on characteristics of GM-BMMs compared to GM-BMDCs in this study.…”

GM-CSF: An immune modulatory cytokine that can suppress autoimmunity

“…In monocytes for example, GM-CSF regulates the expression of TLR2 and has been shown to induce the expression of IL-12, TNF-α, and monocyte chemoattractant protein-1 (MCP-1) by JAK2/STAT5 signaling (82, 83). Similarly, in vitro treatment of macrophage lineage cells with GM-CSF shifts the polarization to an inflammatory M1 phenotype (Fig 1) that enables them to respond strongly to stimuli (84, 85). In contrast, when M-CSF is used as the sole stimulus, it shifts monocytes into an immunosuppressive M2 phenotype (86, 87).…”