Nuclear receptors, the aryl hydrocarbon receptor, and macrophage function

Abstract

Nuclear receptors (NRs) are key regulators of innate immune responses and tissue homeostasis. Evidence indicates that NRs significantly impact steady-state immune regulation, uptake and processing of apoptotic cells, tolerance induction, and control of inflammatory immunity. In this review, we describe our current understanding of the NR activity for balancing inflammation and tolerance, the signaling cascade inducing the NR activation and functional responses, and different mechanisms of the NR-driven immune effects in the context of autoimmune diseases. We further describe the ligand-activated transcription factor the aryl hydrocarbon receptor (AhR) that exhibits analogous functionality. Moreover, we will discuss the putative role of NRs and AhR in immune regulation and disease pathogenesis providing a rationale for therapeutic targeting as a unique opportunities in the clinical management of autoimmune diseases.

Keywords: Aryl hydrocarbon receptor; Autoimmunity; Efferocytosis; Inflammation; Macrophages.

Figure 1.. NRs promote tolerance increasing recognition and degradation of apoptotic cells.

A) NRs directly promote expression of opsonins (e.g. Protein S, MFGE8, GAS6) and expression of specialized receptors (i.e. MERKT, CD36), that recgonize “eat me” signals selectively displayed on the surface of dying cells. Alternatively, NRs like GR or LXRs can indirectly promote efferocytosis by upregulating NRs directly involved in transcription of phagocytic receptors. Up-regulation of phagocytic receptor expression in-turn increases the rate and capacity of efferocytosis. B) NRs promote expression of proteins involved in the efferosome-lysosome or laposome-lysosome pathway (e.g. Rab7, Lamp1, Lamp2, ATG5, ATG7 or BECN1) to boost host defense during mycobacterial infection. NRs might exploit these same pathways to induced efferosome maturation, ensuring complete degradation of apoptotic cells following efferocytosis. Incomplete degradation of apoptotic cells results in accumulation and presentation of autoantigen leading to inflammation and, eventually autoimmune disease.

Figure 2.. NRs control Mϕ polarization and metabolism.

NRs regulate inflammation and tolerance by balancing pro- and anti-inflammatory cytokine/chemokine production (A) and Mϕ metabolism (B). A) NR activation is associated with a suppression of proinflammatory and an augmentation of anti-inflammatory cytokine production by Mϕ, leading to resolution of the inflammatory process. Some NRs like LXR and GR have been shown to have a more plastic role in modulation of inflammation. For example, following acute stimulation, LXR and GR can increase inflammatory maturation of Mϕ amplifying inflammation. In contrast, prolonged stimulation NRs induces alternatively activated Mϕ and a decreased production of chemokines, favouring the resolution of inflammation and immunological tolerance. B) Upper Panel- Inflammatory Mϕ increase use of glycolysis for energy and biosynthetic precursor production. Glycolysis-generated pyruvate then enters a truncated TCA cycle, which it is interrupted at the level of IDH and SDH enzymes, promoting accumulation of citrate and succinate. Increased level of citrate and succinate are required for the generation of ROS and inflammatory genes. Lower panel- Alternatively activated Mϕ significantly increased use of OXPHOS and FAO to produce ATP (lower panel). NRs reprogram Mϕ mitochondrial metabolism rewiring the TCA cycle and increasing FAO. Activation of NRs (i.e. PPR-a, NR4A-1/Nur77 and ESSR-a) down-regulates IDH expression decreasing accumulation of TCA cycle intermediates that drive inflammatory potential of Mϕ. Moreover, NRs activation induce expression of genes controlling lipolysis, fatty acid uptake as well as oxidation boosting FAO.