Immunometabolic Signaling Pathways Contribute to Macrophage and Dendritic Cell Function

Abstract

Understanding of antigen-presenting cell (APC) participation in tissue inflammation and metabolism has advanced through numerous studies using systems biology approaches. Previously unrecognized connections between these research areas have been elucidated in the context of inflammatory disease involving innate and adaptive immune responses. A new conceptual framework bridges APC biology, metabolism, and cytokines in the generation of effective T-cell responses. Exploring these connections is paramount to addressing the rising tide of multi-organ system diseases, particularly chronic diseases associated with metabolic syndrome, infection, and cancer. Focused research in these areas will aid the development of strategies to harness and manipulate innate immunology to improve vaccine development, anti-viral, anti-inflammatory, and anti-tumor therapies. This review highlights recent advances in APC "immunometabolism" specifically related to chronic viral and metabolic disease in humans. The goal of this review is to develop an abridged and consolidated outlook on recent thematic updates to APC immunometabolism in the areas of regulation and crosstalk between metabolic and inflammatory signaling and the integrated stress response and how these signals dictate APC function in providing T-cell activation Signal 3.

FIG. 1

Immunometabolic signaling pathways contribute to regulation of T-cell responses by APCs. (A) Activation signaling for CD4+ T cells; Signal 1 TCR engagement by the MHC:peptide complex; Signal 2 co-stimulatory activation through CD28; and Signal 3-activating cytokine signal provided by IL-1 family members or type I IFN. (B) Inflammatory activation by PAMPS through TLR3 or TLR4; signaling through NF-κB, or IRF3; and induction of inflammatory gene expression. (C) Metabolic activation of transcription factors through oxysterols produced upon cholesterol accumulation (LXR) and induction of metabolic gene expression. Inhibitory interactions are presented in red and are described in the text. Activating interactions are presented in green and are also described in the text.