Regulation of macrophage functions by FABP-mediated inflammatory and metabolic pathways

Abstract

Macrophages are almost everywhere in the body, where they serve pivotal functions in maintaining tissue homeostasis, remodeling, and immunoregulation. Macrophages are traditionally thought to differentiate from bone marrow-derived hematopoietic stem cells (HSCs). Emerging studies suggest that some tissue macrophages at steady state originate from embryonic precursors in the yolk sac or fetal liver and are maintained in situ by self-renewal, but bone marrow-derived monocytes can give rise to tissue macrophages in pathogenic settings, such as inflammatory injuries and cancer. Macrophages are popularly classified as Th1 cytokine (e.g. IFNγ)-activated M1 macrophages (the classical activation) or Th2 cytokine (e.g. IL-4)-activated M2 macrophages (the alternative activation). However, given the myriad arrays of stimuli macrophages may encounter from local environment, macrophages exhibit notorious heterogeneity in their phenotypes and functions. Determining the underlying metabolic pathways engaged during macrophage activation is critical for understanding macrophage phenotypic and functional adaptivity under different disease settings. Fatty acid binding proteins (FABPs) represent a family of evolutionarily conserved proteins facilitating lipid transport, metabolism and responses inside cells. More specifically, adipose-FABP (A-FABP) and epidermal-FABP (E-FABP) are highly expressed in macrophages and play a central role in integrating metabolic and inflammatory pathways. In this review we highlight how A-FABP and E-FABP are respectively upregulated in different subsets of activated macrophages and provide a unique perspective in defining macrophage phenotypic and functional heterogeneity through FABP-regulated lipid metabolic and inflammatory pathways.

Keywords: Fatty acid binding proteins; Inflammation; Macrophages; Obesity.

Figure 1.. A-FABP and E-FABP expression pattern in splenic macrophages.

Splenic macrophages (CD11b⁺F4/80⁺) (A) are divided into four subsets (Q1-Q4) by the surface markers Ly6C and MHCII (B). Individual subsets were separated by a flow sorter and relative levels of A-FABP and E-FABP in each subset were assessed by real-time PCR (C).

Figure 2. Expression of E-FABP and A-FABP in different subsets of TAMs.

E-FABP expression in TAMs exerts anti-tumor effects by promoting type I IFNβ signaling and adaptive immune responses, while TAM expression of A-FABP promotes tumor progression by enhancing pro-tumor IL-6/STAT3 signaling.

Figure 3. A-FABP and E-FABP contribute to atherosclerosis by regulating different subsets of monocytes/macrophages.

A-FABP⁺Ly6C⁻CD36⁺ patrolling monocytes uptake oxLDL and initiate atherosclerotic lesions while recruited Ly6C⁺ CCR2⁺ monocytes express E-FABP, contributing to local inflammation in the atherosclerotic plaque.

Figure 4. A-FABP coordinates FA responses in macrophages.

In A-FABP⁺ macrophages, A-FABP can facilitate multiple FA-mediated responses, which include FA oxidation and ROS production in mitochondria, ceramide production and ER stress, and activation of nuclear transcriptional factors (e.g. PPARγ) activation and regulation of gene expression (e.g. CD36).

Figure 5. E-FABP coordinates FA responses in macrophages.

In E-FABP⁺ macrophages, E-FABP mediates multiple FA-induced responses, including FA oxidation and ROS production, inflammasome activation and IL-1β upregulation, lipid droplet formation and IFNβ responses, and nuclear transcriptional factor activation and gene regulation.