Schistosome and intestinal helminth modulation of macrophage immunometabolism

Abstract

Macrophages are fundamental to sustain physiological equilibrium and to regulate the pathogenesis of parasitic and metabolic processes. The functional heterogeneity and immune responses of macrophages are shaped by cellular metabolism in response to the host's intrinsic factors, environmental cues and other stimuli during disease. Parasite infections induce a complex cascade of cytokines and metabolites that profoundly remodel the metabolic status of macrophages. In particular, helminths polarize macrophages to an M2 state and induce a metabolic shift towards reliance on oxidative phosphorylation, lipid oxidation and amino acid metabolism. Accumulating data indicate that helminth-induced activation and metabolic reprogramming of macrophages underlie improvement in overall whole-body metabolism, denoted by improved insulin sensitivity, body mass in response to high-fat diet and atherogenic index in mammals. This review aims to highlight the metabolic changes that occur in human and murine-derived macrophages in response to helminth infections and helminth products, with particular interest in schistosomiasis and soil-transmitted helminths.

Keywords: helminth; macrophage; metabolic disease; metabolism; schistosome.

Figure 1

Schistosome modulation of tissue and macrophage metabolism. Schistosome‐derived products induce a type‐2 response with secretion of interleukin‐4 (IL‐4), IL‐13, IL‐5, IL‐10 cytokines by eosinophils and lymphocytes. Concomitantly, schistosome products are recognized by pattern recognition receptors in macrophages and induce an alternative activated phenotype, dependent on the signal transducer and activator of transcription 6 (STAT‐6), and reprogramming of metabolism‐related genes. Alternative activation by schistosomes up‐regulates fatty acid oxidation and attenuates lipid accumulation. Up‐regulation of AKT and mTORC1 modulates catabolism and glucose metabolism. Additionally, schistosome‐induce macrophage reprogramming contributes to the metabolic regulation of hepatic and adipose tissue and the protection from high‐fat diet induced weight gain, type 2 diabetes and atherosclerosis. AKT, protein kinase B; mTORC1, mammalian target of rapamycin complex 1.

Figure 2

Soil‐transmitted helminths (STH) and regulation of metabolic homeostasis. Intestinal helminths such as roundworms, whipworms and hookworm lodge in the colon and cecum, elicit a strong type 2 response, and reduce T helper type 1 inflammation by lowering fatty acids in the intestine of infected mammals. Moreover, they induce polarization of macrophages to an alternative activated phenotype, characterized by Arg‐1 and Nos‐2 up‐regulation, downmodulation of pro‐inflammatory factors like IL‐6, TNF‐α, STAT‐3, C/EBPβ, and NFIL3 and secretion of IL‐4, IL‐13 and IL‐5 in macrophages, eosinophils and innate lymphoid cells 2 (ILC2). Infection by STH contributes to changes in the adipose compartment and adipose tissue browning, mediated in part by UCP‐1, which correlates to reduced fat and cholesterol levels and overall improved metabolic index in humans. Arg‐1, arginase‐1; IL‐6, interleukin‐6; Nos‐2, Nitric oxide synthase 2; STAT‐3, signal transducer and activator 3; C/EBPβ, CCAAT‐enhancer‐binding protein; NFIL3, Nuclear Factor, IL‐3 Regulated; TNF‐α, tumor necrosis factor α.