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

doi:10.1016/j.celrep.2020.107825

Abstract

SUMMARYActivated 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.

Highlights

Macrophages are widely distributed with impressive functional diversity (Gordon et al, 2014; Haldar and Murphy, 2014)
Because monocytes and macrophages alter iron metabolism during inflammation (Ganz and Nemeth, 2015), we examined whether inflammation regulates Spic by treating SpicGFP/GFP reporter mice (Haldar et al, 2014) with intraperitoneal LPS
We previously showed that the transcription factor Bach1 constitutively represses Spic expression in monocytes (Haldar et al, 2014)

Summary

Introduction

Macrophages are widely distributed with impressive functional diversity (Gordon et al, 2014; Haldar and Murphy, 2014). Tissue macrophages help maintain local tissue homeostasis (Gordon et al, 2014; Haldar and Murphy, 2014). Injury or infection leads to the recruitment of circulating monocytes that can locally differentiate into macrophages (monocyte-derived macrophages [Mo-MACs]) that produce cytokines and other factors that shape the ensuing immune response. Resolution of inflammation is facilitated by reduced pro-inflammatory and increased anti-inflammatory cytokine production by Mo-MACs (Murray, 2017; Oishi and Manabe, 2018; Wynn and Vannella, 2016). Excessive or prolonged inflammatory responses can impair tissue repair, whereas suboptimal responses lead to poor pathogen control (Murray and Wynn, 2011). Macrophage inflammatory responses are dynamically regulated, but the molecular underpinnings are unclear

Methods

Results

Discussion

Conclusion