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
Affiliations
Zahidul Alam
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
Samir Devalaraja
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
Minghong Li
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
Tsun Ki Jerrick To
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
Ian W. Folkert
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
Erick Mitchell-Velasquez
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
Mai T. Dang
Department of Neurology, The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
Patricia Young
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA; Department of Neurology, The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
Christopher J. Wilbur
Department of Pediatrics, The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
Michael A. Silverman
Department of Pediatrics, The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
Xinyuan Li
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
Youhai H. Chen
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
Paul T. Hernandez
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
Aritra Bhattacharyya
Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
Mallar Bhattacharya
Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
Matthew H. Levine
Department of Surgery, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA
Malay Haldar
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, PA 19104, USA; Corresponding author
Summary: 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.
