Macrophages can adopt diverse functional states in response to environmental cues, a process that is fundamentally controlled at the level of transcriptional regulation. In this review, we outline a hierarchical framework of transcription factor activity that underpins macrophage identity and activation. Firstly, lineage-determining transcription factors establish the cell-type-specific chromatin landscape during development. Upon tissue seeding, local signals shape the activity of additional transcription factors that refine enhancer landscapes and drive tissue-specific macrophage phenotypes. Macrophages further adopt their functional states when exposed to potential threats to tissue homeostasis, such as bacterial ligands or inflammatory cytokines. In response, signal-dependent transcription factors are activated and initiate signal-appropriate transcriptional programs. The specificity and durability of these responses are determined by secondary transcription factors that modulate the magnitude, timing, and maintenance of stimulus-induced transcriptional programs. Collectively, macrophage responses emerge from the activity of interconnected layers of cell-type-, tissue-, and signal-dependent transcription factors, forming complex regulatory networks that inflict stimulus-specific outcomes. Dysregulation of these networks can transcriptionally rewire macrophages toward disease-associated states. Delineating transcriptional regulators that distinguish signal responses may enable more targeted disease interventions. This review discusses how different layers of transcription factor activity cooperate to yield stimulus-specific macrophage responses.
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