Functional Hallmarks of Healthy Macrophage Responses: Their Regulatory Basis and Disease Relevance

Abstract

Macrophages are first responders for the immune system. In this role, they have both effector functions for neutralizing pathogens and sentinel functions for alerting other immune cells of diverse pathologic threats, thereby initiating and coordinating a multipronged immune response. Macrophages are distributed throughout the body-they circulate in the blood, line the mucosal membranes, reside within organs, and survey the connective tissue. Several reviews have summarized their diverse roles in different physiological scenarios and in the initiation or amplification of different pathologies. In this review, we propose that both the effector and the sentinel functions of healthy macrophages rely on three hallmark properties: response specificity, context dependence, and stimulus memory. When these hallmark properties are diminished, the macrophage's biological functions are impaired, which in turn results in increased risk for immune dysregulation, manifested by immune deficiency or autoimmunity. We review the evidence and the molecular mechanisms supporting these functional hallmarks.

Keywords: IRF; MAPK; NF-κB; chromatin; epigenetic memory; innate immunity; interferon; macrophages; polarization; sentinel cells; stimulus specificity.

Figure 1

Functional hallmarks of macrophages. (a) Macrophages respond by performing a variety of functions. Categorization of these functions show that macrophages can perform as sentinel cells of the immune system or as immune effector cells. (b) Macrophage responses exhibit three hallmarks central to immunological function: Response Specificity, Context Dependence, and Stimulus Memory. Dashed and solid arrows represent deployment of specific functions to different degrees or speeds.

Figure 2

Mechanisms and measurement approaches of Response Specificity. (a) Response Specificity relies on the ability of dozens of pathogen recognition receptors and cytokine receptors to recognize specific ligands. Ligand-receptor interactions activate specific signaling pathways with ligand-specific temporal and dose dynamics, which are recognized by gene regulatory mechanisms that decode the stimulus-specific combinations of temporally modulated transcription factor activities. Single cell heterogeneity in signaling network activation and transcriptional regulation all impact Response Specificity. (b) Single-cell measurements of signaling or epigenetic events that can be interrogated to quantify Response Specificity, (c) resulting in an understanding of ligand-response distributions in health versus disease. Abbreviations: ATAC-seq, assay for transposase-accessible chromatin with sequencing; FISH, fluorescence in situ hybridization; RNA-seq, RNA sequencing; PRR, pattern recognition receptor; TNFR, Tumor necrosis factor receptor; IFNAR, interferon alpha/beta receptor; AP1, activator protein 1; ATFs, Activating transcription factors; NFκB, nuclear factor kappa B; IRFs, interferon response factors; ISGF3, interferon stimulated gene factor 3; STATs, signal transducer and activator of transcription.

Figure 3

Context Dependence is mediated by microenvironmental signals that may lead to a canalization of the diverse stimulus-specific macrophage responses. (a) Cytokine context results in specialization of function by reversibly altering the epigenetic states of signaling and gene regulatory networks. Arrows pointing to regions of the response landscape represent possible responses given an inflammatory stimulus. (b) Positive and negative regulation of signaling feedback regulators by polarizing cytokines may generate context-dependent signaling profiles. (c) Epigenetic mechanisms that either hold open promoters or disassemble enhancers allow for gene-specific regulation of context-dependent responses in macrophages. Abbreviations: PRR, pattern recognition receptor; IFNGR, interferon gamma receptor.

Figure 4

Stimulus Memory involves prior exposure altering epigenetic states of signaling and gene regulatory networks. (a) Stimulus Memory is mediated for example by changes to the chromatin enhancer landscape, altering response potential after the initial stimulus has subsided. Arrows pointing to regions of the response landscape represent possible responses given an inflammatory stimulus. (b) Stimulus-specific non-oscillatory activity of SDTFs opens chromatin in collaboration with cofactors and chromatin-remodeling enzymes. (c) Both signaling pathway activation and alterations to metabolic pathway activity are critical arms for generating innate immune memory. Abbreviations: HAT, histone acetyltransferase; HMT, histone methyltransferase; SDTF, signal-dependent transcription factor; TCA, tricarboxylic acid; NFκB, nuclear factor kappa B; PU.1, PU-box binding factor.