Safeguard function of PU.1 shapes the inflammatory epigenome of neutrophils.
Josephine FischerCarolin WalterAlexander TöngesHanna AlethMarta Joana Costa JordaoMathias LeddinVerena GröningTabea ErdmannGeorg LenzJohannes RothThomas VoglMarco PrinzMartin DugasIlse Denise JacobsenFrank RosenbauerPublished in: Nature immunology (2019)
Neutrophils are essential first-line defense cells against invading pathogens, yet when inappropriately activated, their strong immune response can cause collateral tissue damage and contributes to immunological diseases. However, whether neutrophils can intrinsically titrate their immune response remains unknown. Here we conditionally deleted the Spi1 gene, which encodes the myeloid transcription factor PU.1, from neutrophils of mice undergoing fungal infection and then performed comprehensive epigenomic profiling. We found that as well as providing the transcriptional prerequisite for eradicating pathogens, the predominant function of PU.1 was to restrain the neutrophil defense by broadly inhibiting the accessibility of enhancers via the recruitment of histone deacetylase 1. Such epigenetic modifications impeded the immunostimulatory AP-1 transcription factor JUNB from entering chromatin and activating its targets. Thus, neutrophils rely on a PU.1-installed inhibitor program to safeguard their epigenome from undergoing uncontrolled activation, protecting the host against an exorbitant innate immune response.
Keyphrases
- immune response
- transcription factor
- dna methylation
- dendritic cells
- histone deacetylase
- gene expression
- signaling pathway
- genome wide identification
- toll like receptor
- genome wide
- induced apoptosis
- oxidative stress
- dna binding
- gram negative
- bone marrow
- cell cycle arrest
- dna damage
- copy number
- cell death
- antimicrobial resistance
- cell proliferation
- inflammatory response
- multidrug resistant
- high fat diet induced
- quality improvement
- pi k akt
- adipose tissue
- endoplasmic reticulum stress
- cell wall