PPARδ activation in microglia drives a transcriptional response that primes phagocytic function while countering inflammatory activation
Authors:
- Jacob S DeyellJDJacob S Deyell
- Jonathan HasselmannJHJonathan Hasselmann
- Linda StroudLSLinda Stroud
- Urmimala RaychaudhuriURUrmimala Raychaudhuri
- Yunzi GuoYGYunzi Guo
- Byeonggu ChaBCByeonggu Cha
- Christopher KarmaCKChristopher Karma
- Deavin TendeanDTDeavin Tendean
- Minh-Huy Vu TranMTMinh-Huy Vu Tran
- Anastasia GromovaAGAnastasia Gromova
- Audrey S DickeyADAudrey S Dickey
- Matthew Blurton-JonesMBMatthew Blurton-Jones
Preprint
Abstract
Microglia have been implicated in neurodegeneration, though their role remains unclear, as microglia can perform protective functions or promote neuroinflammation. Numerous studies have found that the transcriptome state of microglia can indicate where they lie along this continuum. To understand regulation of microglia transcriptome state, we considered the transcription factor PPARδ, because it is highly expressed in microglia and is a therapeutic target for Alzheimer's disease, (AD) a neurodegenerative disorder characterized by progressive memory loss where microglia dysfunction is involved. When we delineated the microglia transcriptome in mice treated with PPARδ agonist, we noted that PPARδ activation blunted expression of inflammatory mediators and migration-enhancing genes, while boosting phagocytic genes. We then examined PPARδ function in induced transcription factor (iTF) microglia-like cells, and confirmed PPARδ agonism increases phagocyte function while reducing pro-inflammatory cytokines and migration. To understand PPARδ regulation upon CNS insult, we exposed iTF-microglia to apoptotic neuron debris and defined six microglia transcriptome states as a function of PPARδ activation, and observed PPARδ agonism can shift microglia out of a homeostatic state to a primed, disease-associated microglia-like state. As PPARδ agonism opposed gene expression favored by PU.1, a critical transcription factor in microglial inflammation and AD pathogenesis, we examined their relationship, documented a physical interaction, and found evidence for transrepression. Finally, we tested PPARδ agonism in Huntington's disease and tauopathy mice, and demonstrated PPARδ could decrease neuroinflammation in vivo. These findings suggest that PPARδ agonist therapy may mitigate microglial dysfunction by restoring beneficial functions, while suppressing detrimental inflammation.Keywords
Funding Information
- National Institutes of Health (F30AG081084)
- National Institutes of Health (R35NS122140)
- National Institutes of Health (RF1AG033082)