Macrophage polarization and meta-inflammation

Abstract

Chronic overnutrition and obesity induces low-grade inflammation throughout the body. Termed "meta-inflammation," this chronic state of inflammation is mediated by macrophages located within the colon, liver, muscle, and adipose tissue. A sentinel orchestrator of immune activity and homeostasis, macrophages adopt variable states of activation as a function of time and environmental cues. Meta-inflammation phenotypically skews these polarization states and has been linked to numerous metabolic disorders. The past decade has revealed several key regulators of macrophage polarization, including the signal transducer and activator of transcription family, the peroxisome proliferator-activated receptor gamma, the CCAAT-enhancer-binding proteins (C/EBP) family, and the interferon regulatory factors. Recent studies have also suggested that microRNAs and long noncoding RNA influence macrophage polarization. The pathogenic alteration of macrophage polarization in meta-inflammation is regulated by both extracellular and intracellular cues, resulting in distinct secretome profiles. Meta-inflammation-altered macrophage polarization has been linked to insulin insensitivity, atherosclerosis, inflammatory bowel disease, cancer, and autoimmunity. Thus, further mechanistic exploration into the skewing of macrophage polarization promises to have profound impacts on improving global health.

Figure 1. Intracellular and Extracellular miRNA profile of BMDMs

(a) Total extracellular RNAs (exRNAs) were extracted from conditioned medium of BMDMs 48 hours post-stimulation and intracellular RNAs (inRNAs) were extracted from the same batch of BMDMs. qRT-PCR analysis confirmed that miR-150 and miR-744 were highly expressed in the BMDMs, but secreted at low levels. Interestingly, miR-223, a potent regulator of macrophage polarization, was abundant in both the intra- and extra-cellular compartment. (b) BMDMs were either not activated (M0) or stimulated with 100 ng/mL LPS (M1) or 20 ng/mL IL-4 (M2). Total extracellular RNAs were extracted from cell culture supernatants 24 hours post-stimulation and miR-223 expression was quantified by qRT-PCR. exRNAs were normalized using Cel-miR-39 as spike-in controls. Data are presented as mean ± SEM; n=4, *, p<0.05 (student’s t test).

Figure 2. Macrophage polarization modulated tissue/organ functions during obesity-induced metainflammation

Obesity-associated metainflammation orchestrates macrophage polarization patterns through altering environmental cues, which generally favors an M1 activation state. M1- and M2-like macrophages differently modulate tissue/organ functions by secreting specific cytokines and/or reactive chemical species. Metainflammation-altered macrophage polarization profiles contribute to local tissue pathology at sites such as liver, colon and arterial walls, and further impose systemic effects by regulating insulin sensitivity in the liver, muscle and adipose tissues.