Macrophage Alternative Activation Confers Protection Against Lipotoxicity-induced Cell Death

Immune cells, such as macrophages, dendritic cells and a number of other effector cells are involved in the important human host mechanism against external threats. Macrophages function in both innate (non-specific) and adaptive (specific) immunity in vertebrate animals. Based on their functional importance, they can be divided into classically activated macrophages (also known as M1) and alternatively activated macrophages (also known as M2).Obesity is one of the major threats to human health in the21st century. It presents a low grade inflammatory and can progress to other metabolic diseases including insulin resistance, type II diabetes, fatty liver, atherosclerosis and hypertension. Recent evidence indicates that macrophages are key players in the progression of metabolic diseases.Alternative activation of adipose tissue resident macrophages (ATM) reduces obesity-induced metabolic inflammation and insulin resistance. The molecular detail of this protective effect remains unclear. Here we show that alternatively activated (M2) macrophages are protected from cellular dysfunction caused by lipid overload which can, at least partially explain the protective effect of M2macrophages during obesity. The major findings in this paper are:1. Cross-comparisons of genes regulated two M2inducers, interleukin-4(IL-4) or peroxisome proliferator-activated receptor delta/gamma (PPARs/PPARy) agonists, reveal that alternative activation promotes the cell survival program while inhibiting that of apoptosis. PPAR signaling also controls pathways that direct fatty acids toward storage, oxidation and biosynthesis of lipid mediators.2. In cultured macrophages, deletion of PPARδ/PPARγ or (signal transducer and activator of transcription6) STAT6(a downstream effector of IL-4) genes increases the susceptibility to palmitic acid-induced necrotic cell death. In concert, higher levels of caspase-3activities are detected in ATMs derived from myeloid-specific PPARδ/γ-/-or STAT6-/-mice either challenged with a high fat diet or p-adrenergic agonist.3. At the molecular level, Angptl4and Notch4are identified as PPAR targets in the survival pathway. Angptl4-/-or Notch4-/-macrophages are shown to be more prone to death after palmitic acid treatment.4. Palmitic acid induced macrophage death is sufficient to cause inflammatory response and this response can be amplified by crosstalk between macrophages and adipocytes, which may contribute to the initiation of inflammation during obesity.