The mononuclear phagocyte system regulates tissue homeostasis as well as all phases of tissue injury and repair. To do so changing tissue environments alter the phenotype of tissue macrophages to assure their support for sustaining and amplifying their respective surrounding environment. Interferon-regulatory factors are intracellular signaling elements that determine the maturation and gene transcription of leukocytes. Here we discuss how several among the 9 interferon-regulatory factors contribute to macrophage polarization. 1. Introduction During development mononuclear phagocyte progenitors populate most tissues where they differentiate into transcriptionally and functionally diverse phenotypes [1–3]; for example, bone marrow, liver, and lung harbor macrophages with an enormous capacity to clear airborne particles, gut-derived pathogens, or cell nuclei expelled from erythroblasts, respectively [4]. In contrast, skin, kidney, and brain host a dense network of dendritic cells [4, 5]. Upon tissue injury M-CSF drives resident mononuclear phagocyte to proliferate [6] or circulating monocytes recruit to the site of injury. It is the local microenvironment that then determines mononuclear phagocyte polarization to distinct phenotypes, which can vary between disorders or between the different stages of a disease process [7]. Several factors mediate mononuclear phagocyte polarization, as being mostly described by in vitro experiments [7, 8]. However, attempts to translate this simplistic model to disease states in vivo often failed to cover all aspects of heterogeneous and changing tissue environments. For example, ischemia-reperfusion injury induces transient sterile inflammation because dying tissue cells release damage-associated molecular patterns (DAMPs) that polarize macrophages toward a classically activated M1-like phenotype [9, 10]. This process is associated with NF-κB and STAT1 pathway activation [2]. Macrophages apoptosis or their phenotype switches towards alternatively activated, M2-like macrophages that produce IL-10 and TGF-β, induce resolution of inflammation, and enforce tissue regeneration [11–15]. Failure of this phenotype switch leads to persistent tissue inflammation, atrophy, and fibrosis [16]. The uptake of neutrophils, epithelium-derived alarmins, and Th2 cytokines IL-4 and IL-13 supports this phenotype switch [11]. As disease processes do not always occur in a serial manner, concomitant proinflammatory and anti-inflammatory macrophages infiltrates often populate organs affected by persistent injury, for example, in slowly
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