Palmitate Conditions Macrophages for Enhanced Responses toward Inflammatory Stimuli via JNK Activation

Abstract

Obesity is associated with low-grade inflammation and elevated levels of circulating saturated fatty acids, which trigger inflammatory responses by engaging pattern recognition receptors in macrophages. Because tissue homeostasis is maintained through an adequate balance of pro- and anti-inflammatory macrophages, we assessed the transcriptional and functional profile of M-CSF-dependent monocyte-derived human macrophages exposed to concentrations of saturated fatty acids found in obese individuals. We report that palmitate (C16:0, 200 μM) significantly modulates the macrophage gene signature, lowers the expression of transcription factors that positively regulate IL-10 expression (MAFB, AhR), and promotes a proinflammatory state whose acquisition requires JNK activation. Unlike LPS, palmitate exposure does not activate STAT1, and its transcriptional effects can be distinguished from those triggered by LPS, as both agents oppositely regulate the expression of CCL19 and Besides, palmitate conditions macrophages for exacerbated proinflammatory responses (lower IL-10 and CCL2, higher TNF-α, IL-6, and IL-1β) toward pathogenic stimuli, a process also mediated by JNK activation. All of these effects of palmitate are fatty acid specific because oleate (C18:1, 200 μM) does not modify the macrophage transcriptional and functional profiles. Therefore, pathologic palmitate concentrations promote the acquisition of a specific polarization state in human macrophages and condition macrophages for enhanced responses toward inflammatory stimuli, with both effects being dependent on JNK activation. Our results provide further insight into the macrophage contribution to obesity-associated inflammation.

Size matters: Effect of granule size of the bone graft substitute (Herafill®) on bone healing using Masquelet's induced membrane in a critical size defect model in the rat's femur

“…Herafill® granules consist of calcium sulfate, calcium carbonate and glycerine tripalmitate as bonding additive (Heraeus Medical GmbH, ). Palmitate is a saturated nonesterified fatty acid (NEFA) which is known to induce a proinflammatory and immunogenic response in human monocytes and cause synthesis and secretion of IL‐6 and TNF‐α (Bunn et al, ; Riera‐Borrull et al, ). Furthermore, palmitate increases the secretion of proinflammatory adipokines monocyte chemoattractant protein‐1 (MCP‐1) and vascular endothelial growth factor (VEGF) (Kitahara et al, ).…”

“…Furthermore, it could be evidenced that increased palmitate‐concentration has impact on the polarization of macrophages and their reactivity on inflammatory stimuli via activation of JNK‐kinases (Riera‐Borrull et al, ). Also, evidence is found that high doses of palmitate significantly influence the differentiation of bone marrow‐derived macrophages and promote the anti‐inflammatory M2‐subtype.…”

The role of macrophages in obesity-associated islet inflammation and β-cell abnormalities

“…In vitro incubation of mouse and human monocyte/macrophage cell lines in media containing high concentrations of glucose or free fatty acids (FFAs) induces increased IL-1β production. This suggests that metabolic stress in obesity and/or T2DM can stimulate islet macrophages to produce more IL-1β 10,65,66 . Indeed, while both β-cells and macrophages can produce IL-1β, macrophages are seemingly the major source of islet IL-1β production in obesity 10,64 .…”

Defining tissue- and disease-associated macrophages using a transcriptome-based classification model

“…We investigated whether macIDR was capable of discerning GM-CSF-differentiated MDMs (GM-MDMs) exposed to various stimuli. In total, we obtained 31 datasets from three microarray studies ( 5, 16, 39 ) where GM-MDMs were activated with LPS (GM-LPS early , GM-LPS late ), IFNγ (GM-IFNγ), and IL4 (GM-IL4), or remained unstimulated (GM0). These studies were selected based on their similarity in activation duration with the M-CSF differentiated macrophages used in the training set.…”

“…To understand the limitations of macIDR, we investigated its performance on non-MDM cells. Datasets were obtained of monocyte-derived dendritic cells (MoDC) ( 5, 39 ), various T lymphocyte subtypes (T), B lymphocytes (B), neutrophils (NP), and natural killer cells (NK) ( 16, 40 ), as well as fibroblast-like synoviocytes (FLS) ( 27 ).…”