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PPARg T166 phosphorylation-mediated lipid synthesis sustains the reparative function of macrophages during tissue repair

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE269834 | GEO | 2024/07/30

REPOSITORIES: GEO

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PPARg T166 phosphorylation-mediated lipid synthesis sustains the reparative function of macrophages during tissue repair [RNA-seq]

Project description:Macrophages exhibit a reparative phenotype that supports tissue repair and remodeling in response to tissue injury. However, the metabolic requirements that support this process have remained incompletely understood. Here, we showed that posttranslational modification (PTM) of peroxisome proliferator-activated receptor g (PPARg) regulated lipid synthesis in response to wound microenvironmental cues and that metabolic rewiring orchestrated the function of reparative macrophages. In injured tissues, repair signaling attenuated macrophage PPARg threonine 166 (T166) phosphorylation, which induced a partially active PPARg program with increased binding activity to the regulator regions of lipid synthesis-associated genes, thereby activating lipogenesis. The accumulated lipids served as signaling molecules, triggering signal transducer and activator of transcription 3 (STAT3)-mediated growth factor expression, and supporting the synthesis of phospholipids for the expansion of the endoplasmic reticulum (ER), which is required for the secretion of proteins. Genetic or pharmacological inhibition of PPARg T166 phosphorylation promoted the reparative function of macrophages and facilitated tissue regeneration. In summary, we identified that PPARg T166-regulated lipid biosynthesis was essential for the anabolic demands of the activation and function of macrophages and provided a rationale for therapeutic targeting of tissue repair.

2024-07-30 | GSE252899 | GEO

PPARg T166 phosphorylation-mediated lipid synthesis sustains the reparative function of macrophages during tissue repair [ChIP-seq]

2024-07-30 | GSE252900 | GEO

PPARg T166 phosphorylation-mediated lipid synthesis sustains the reparative function of macrophages during tissue repair [CUT&RUN]

2024-07-30 | GSE269832 | GEO

Lipid synthesis, triggered by PPARγ T166 dephosphorylation, sustains reparative function of macrophages during tissue repair.

Project description:Macrophages may acquire a reparative phenotype that supports tissue repair and remodeling in response to tissue injury. However, the metabolic requirements underpinning this process are incompletely understood. Here, we show that posttranslational modification (PTM) of PPARγ regulates lipid synthesis in response to wound microenvironmental cues and that metabolic rewiring orchestrates function of reparative macrophages. In injured tissues, repair signaling leads to decreased macrophage PPARγ threonine 166 (T166) phosphorylation, which results in a partially active PPARγ transcriptional program comprised of increased binding activity to the regulator regions of lipid synthesis-associated genes, thereby increased lipogenesis. The accumulated lipids serve as signaling molecules, triggering STAT3-mediated growth factor expression, and supporting the synthesis of phospholipids for the expansion of the endoplasmic reticulum (ER), which is required for protein secretion. Genetic or pharmacological inhibition of PPARγ T166 phosphorylation promotes the reparative function of macrophages and facilitates tissue regeneration. In summary, our work identifies PPARγ T166-regulated lipid biosynthesis as an essential pathway for meeting the anabolic demands of the activation and function of macrophages and provides a rationale for potential therapeutic targeting of tissue repair.

| S-EPMC11343878 | biostudies-literature

PPARg T166 phosphorylation-mediated lipid synthesis sustains the reparative function of macrophages during tissue repair

Project description:PPARg T166 phosphorylation-mediated lipid synthesis sustains the reparative function of macrophages during tissue repair

| PRJNA1123756 | ENA

PPARg T166 phosphorylation-mediated lipid synthesis sustains the reparative function of macrophages during tissue repair [CUT&RUN]

Project description:PPARg T166 phosphorylation-mediated lipid synthesis sustains the reparative function of macrophages during tissue repair [CUT&RUN]

| PRJNA1123759 | ENA

PPARg T166 phosphorylation-mediated lipid synthesis sustains the reparative function of macrophages during tissue repair [RNA-seq]

Project description:PPARg T166 phosphorylation-mediated lipid synthesis sustains the reparative function of macrophages during tissue repair [RNA-seq]

| PRJNA1063197 | ENA

PPARg T166 phosphorylation-mediated lipid synthesis sustains the reparative function of macrophages during tissue repair [ChIP-seq]

Project description:PPARg T166 phosphorylation-mediated lipid synthesis sustains the reparative function of macrophages during tissue repair [ChIP-seq]

| PRJNA1063196 | ENA

Maresin-like lipid mediators are produced by leukocytes and platelets and rescue reparative function of diabetes-impaired macrophages.

Project description:Nonhealing diabetic wounds are associated with impaired macrophage (Mf) function. Leukocytes and platelets (PLT) play crucial roles in wound healing by poorly understood mechanisms. Here we report the identification and characterization of the maresin-like(L) mediators 14,22-dihydroxy-docosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acids, 14S,22-diHDHA (maresin-L1), and 14R,22-diHDHA (maresin-L2) that are produced by leukocytes and PLT and involved in wound healing. We show that 12-lipoxygenase-initiated 14S-hydroxylation or cytochrome P450 catalyzed 14R-hydroxylation and P450-initiated ω(22)-hydroxylation are required for maresin-L biosynthesis. Maresin-L treatment restores reparative functions of diabetic Mfs, suggesting that maresin-Ls act as autocrine/paracrine factors responsible for, at least in part, the reparative functions of leukocytes and PLT in wounds. Additionally, maresin-L ameliorates Mf inflammatory activation and has the potential to suppress the chronic inflammation in diabetic wounds caused by activation of Mfs. These findings provide initial insights into maresin-L biosynthesis and mechanism of action and potentially offer a therapeutic option for better treatment of diabetic wounds.

| S-EPMC4224612 | biostudies-literature

Blockage of PPARg T166 phosphorylation enhances the inducibility of beige adipocytes and improves metabolic dysfunctions

Project description:Beige adipocytes in mammalian white adipose tissue (WAT) can reinforce fat catabolism and energy expenditure. Promoting beige adipocyte biogenesis is a tantalizing tactic for combating obesity and its associated metabolic disorders. Here, we report that a previously unidentified phosphorylation pattern (Thr166) in the DNA-binding domain of PPARg regulates the inducibility of beige adipocytes. This unique posttranslational modification (PTM) pattern influences allosteric communication between PPARg and DNA or coactivators, which impedes the PPARg-mediated transactivation of beige cell-related gene expression in WAT. The genetic mutation mimicking T166 phosphorylation (p-T166) hinders the inducibility of beige adipocytes. In contrast, genetic or chemical intervention in this PTM pattern favors beige cell formation. Moreover, inhibition of p-T166 attenuates metabolic dysfunction in obese mice. Our results uncover a mechanism involved in beige cell fate determination. Moreover, our discoveries provide a promising strategy for guiding the development of novel PPARg agonists for the treatment of obesity and related metabolic disorders.

2022-10-28 | GSE158615 | GEO

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