STAT6 Signaling Mediates PPARγ Activation and Resolution of Acute Sterile Inflammation in Mice

Abstract

The signal transducer and activator of transcription 6 (STAT6) transcription factor promotes activation of the peroxisome proliferator-activated receptor gamma (PPARγ) pathway in macrophages. Little is known about the effect of proximal signal transduction leading to PPARγ activation for the resolution of acute inflammation. Here, we studied the role of STAT6 signaling in PPARγ activation and the resolution of acute sterile inflammation in a murine model of zymosan-induced peritonitis. First, we showed that STAT6 is aberrantly activated in peritoneal macrophages after zymosan injection. Utilizing STAT6−/− and wild-type (WT) mice, we found that STAT6 deficiency further enhanced zymosan-induced proinflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-6, and macrophage inflammatory protein-2 in peritoneal lavage fluid (PLF) and serum, neutrophil numbers and total protein amount in PLF, but reduced proresolving molecules, such as IL-10 and hepatocyte growth factor, in PLF. The peritoneal macrophages and spleens of STAT6−/− mice exhibited lower mRNA and protein levels of PPARγ and its target molecules over the course of inflammation than those of WT mice. The deficiency of STAT6 was shown to impair efferocytosis by peritoneal macrophages. Taken together, these results suggest that enhanced STAT6 signaling results in PPARγ-mediated macrophage programming, contributing to increased efferocytosis and inflammation resolution.

Transcriptional and Histochemical Signatures of Bone Marrow Mononuclear Cell-Mediated Resolution of Synovitis

“…Examples include shifting the production of pro-inflammatory cytokines towards anti-inflammatory and pro-resolving mediators, driving apoptosis and clearance of neutrophils, enhancing macrophage traffic, recruitment, phagocytosis and efferocytosis, improving mitochondrial respiratory performance, and the overall transcriptome of a regulatory response driving recovery of homeostasis (43,47,101,108). Of note, some isoprenoids, the signature of the blue module, as well as some specialized pro-resolving molecules, signal through PPAR-g, conferring increased production of IL-10, resistance to inflammatory stimuli and attenuated NF-ƙB activation following LPS stimulation (43,81,(109)(110)(111). Gene expression for PPARG was higher in ISF compared to SF.…”

Aurantiamide promotes M2 polarization of microglial cells to improve the cognitive ability of mice with Alzheimer's disease

“…STAT6 is the major IL‐4 mediated pathway (Kaplan et al, 1996), and the JAK/STAT6 pathway is also the main pathway to transfer signals from cell membrane to nucleus. Moreover, the coordination of PPAR and STAT6 can regulate numerous M2 marker genes and construct the STAT6/PPAR pathway (Lee et al, 2021), which is necessary for the M2 polarization and maturation of macrophages. At the same time, STAT3 signal is the regulatory signal for M1 polarization, which has opposite effect to STAT6, while STAT3 is regulated by SOCS3.…”

The role of foam cells in spinal cord injury: challenges and opportunities for intervention

“…After IL-4 and IL-13 bind to their respective receptors (IL-4Rα vs. IL-13Rα), the subsequent activation of the M2 cells largely depends on STAT6, which is transcriptionally activated to upregulate fatty acid β-oxidation, OXPHOS and metabolic genes essential for mitochondrial biogenesis ( 12 ). Additionally, STAT6 induces the expression of transcriptional regulatory proteins and co-activator proteins, such as PPARγ, PPARδ and PGC-1β, which cooperate with STAT6 to sustain the switch of the cellular metabolic profile to oxidative metabolism ( 12 – 15 ). Different metabolic profiles of the M1 and M2 phenotypes stem from this, with the M1 macrophage using Warburg metabolism and the M2 macrophage using OXPHOS, which has been extensively discussed by others in the literature ( 16 – 19 ).…”