Chronic exposure to TGFβ1 regulates myeloid cell inflammatory response in an IRF7-dependent manner

Area of Science:

• Neuroimmunology
• Cellular Biology
• Molecular Biology

Background:

• The central nervous system (CNS) microenvironment dictates myeloid cell function.
• Resident microglia and infiltrating macrophages exhibit distinct pathological activities.
• Molecular mechanisms regulating these differences remain largely unknown.

Purpose of the Study:

• To elucidate the molecular mechanisms by which the tissue microenvironment regulates myeloid cell phenotypes in the CNS.
• To investigate the role of transforming growth factor-β1 (TGFβ1) in myeloid cell polarization.
• To identify key transcription factors involved in the pro- to anti-inflammatory myeloid cell switch.

Main Methods:

• Genome-wide expression analysis.
• Chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq).
• RNA interference (RNAi)-mediated perturbation and interferon-beta 1 (IFNβ1) treatment in myeloid cells.
• In vivo studies following spinal cord injury.

Main Results:

• Prolonged TGFβ1 exposure impairs myeloid cells' ability to adopt an anti-inflammatory phenotype.
• Interferon regulatory factor 7 (IRF7) is identified as a key transcription factor controlling the M1-to-M2 phenotype switch.
• TGFβ1 down-regulates IRF7 expression, inhibiting the M1-to-M2 switch.
• IFNβ1 restores the M1-to-M2 switch, while Irf7 inhibition blocks it.
• In vivo induction of Irf7 in microglia reduces pro-inflammatory activity post-spinal cord injury.

Conclusions:

• The TGFβ1 pathway, via IRF7 down-regulation, critically controls myeloid cell polarization in the CNS.
• IRF7 is a crucial mediator for myeloid cells to transition from a pro-inflammatory to an anti-inflammatory state.
• Targeting the TGFβ1-IRF7 axis presents a potential therapeutic strategy for CNS inflammatory diseases.