Counter Regulation of Spic by NF-κB and STAT Signaling Controls Inflammation and Iron Metabolism in Macrophages

Zahidul Alam, Samir Devalaraja, Minghong Li, Tsun Ki Jerrick To, Ian W. Folkert, Erick Mitchell-Velasquez, Mai T. Dang, Patricia Young, Christopher J. Wilbur, Michael A. Silverman, Xinyuan Li, Youhai H. Chen, Paul T. Hernandez, Aritra Bhattacharyya, Mallar Bhattacharya, Matthew H. Levine, Malay Haldar

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Activated macrophages must carefully calibrate their inflammatory responses to balance efficient pathogen control with inflammation-mediated tissue damage, but the molecular underpinnings of this “balancing act” remain unclear. Using genetically engineered mouse models and primary macrophage cultures, we show that Toll-like receptor (TLR) signaling induces the expression of the transcription factor Spic selectively in patrolling monocytes and tissue macrophages by a nuclear factor κB (NF-κB)-dependent mechanism. Functionally, Spic downregulates pro-inflammatory cytokines and promotes iron efflux by regulating ferroportin expression in activated macrophages. Notably, interferon-gamma blocks Spic expression in a STAT1-dependent manner. High levels of interferon-gamma are indicative of ongoing infection, and in its absence, activated macrophages appear to engage a “default” Spic-dependent anti-inflammatory pathway. We also provide evidence for the engagement of this pathway in sterile inflammation. Taken together, our findings uncover a pathway wherein counter-regulation of Spic by NF-κB and STATs attune inflammatory responses and iron metabolism in macrophages.

Original languageEnglish
Article number107825
JournalCell Reports
Volume31
Issue number13
DOIs
StatePublished - Jun 30 2020

Keywords

  • Bach1
  • NF-κB
  • Spic
  • ferroportin
  • interferon-gamma
  • macrophages
  • monocytes

Fingerprint

Dive into the research topics of 'Counter Regulation of Spic by NF-κB and STAT Signaling Controls Inflammation and Iron Metabolism in Macrophages'. Together they form a unique fingerprint.

Cite this