Non-traditional cytokines: How catecholamines and adipokines influence macrophages in immunity, metabolism and the central nervous system

Abstract

Catecholamines and adipokines function as hormones; catecholamines as neurotransmitters in the sympathetic nervous system, and adipokines as mediators of metabolic processes. It has become increasingly clear, however, that both also function as immunomodulators of innate and adaptive immune cells, including macrophages. Macrophages can respond to, as well as produce their own catecholamines. Dopamine, noradrenaline, and adrenaline are the most abundant catecholamines in the body, and can induce both pro-inflammatory and anti-inflammatory immune responses in macrophages, as well as non-immune processes such as thermogenesis. Though they are responsive to adipokines, particularly lipoproteins, leptin, and adiponectin, macrophages generally do not synthesize their own adipokines, with the exception being resistin-like molecules. Adipokines contribute to adverse metabolic and immune responses by stimulating lipid accumulation, foam cell formation and pro-inflammatory cytokine production in macrophages. Adipokines can also promote balance or resolution during metabolic and immune processes by promoting reverse lipid transport and expression of Th2 cytokines. This review will explore the mechanisms by which catecholamines and adipokines influence macrophage function in neural pathways, immunity and metabolism.

Keywords: Adipokine; Atherosclerosis; Dopamine; Macrophage; Resistin-like molecules.

Figure 1. Catecholamine signaling in macrophage function

A. Catecholamines are recognized by α and β-adrenergic receptors (1). Signaling through α-adrenergic receptors is pro-inflammatory and promotes LPS-induced gene expression whereas β-adrenergic receptor signaling inhibits this and induces expression of anti-inflammatory cytokines (2). Cold temperature induces macrophage synthesis of catecholamines which act to increase white to beige adipose tissue conversion and energy expenditure (3). B. Sciatic and vagus nerve stimulation promotes dopamine synthesis (1). Dopamine receptor signaling enhances GPCR activity leading to increased viral entry and replication (2). Dopamine signaling also inhibits pro-inflammatory cytokine production (3).

Figure 2. Adipokine influence on macrophage function

In addition to influencing the metabolic status of macrophages, adipokines and lipoproteins also exert both pro-inflammatory and anti-inflammatory effects on macrophages.

Figure 3. Resistin-like molecules influence macrophage physiology during in infection and metabolic disease

In general, RELM proteins promote pro-inflammatory responses during infection and metabolic dysfunction, leading to detrimental effects on the host. In some cases, however, the presence of RELM proteins can be beneficial, such as RELMβ promoting resolution of Nippostrongylus infection.