Exploring the mechanism and crosstalk between IL-6 and IL- 1β on M2 macrophages under metabolic stress conditions.

Macrophages are highly variable immune cells that are important in controlling inflammation and maintaining tissue balance. The ability to polarize into two major types-M1, promoting inflammation, and M2, resolving inflammation and contributing to tissue repair-determines their specific roles in health and disease. M2 macrophages are particularly important for reducing inflammation and promoting tissue regeneration, but their function is shaped mainly by surrounding cells. This is evident in obesity, diabetes, and chronic inflammation. Although many cytokines regulate macrophage polarization, interleukin-6 (IL-6) and interleukin-1β (IL-1β) are major players, but their effects on M2 macrophage behavior under metabolic stress remain unclear. This study describes the intricacies within M2 macrophages concerning IL-6 and IL-1β signaling when under metabolic stress. Though, more frequently than not, IL-6 is labelled as pro-inflammatory, it can also behave as an anti-inflammatory mediator. On the other hand, IL-1β is the main pro-inflammatory agent, particularly in metabolic disorders. The relationship between these cytokines and the macrophages is mediated through important pathways such as JAK/STAT and NFκB, which get perturbed by metabolic stress. Therefore, metabolic stress also alters the functional parameters of macrophages, including alterations in mitochondrial metabolism, glycolytic and oxidative metabolism. Phosphorylation alters the kinetics involved in energy consumption and affects their polarization and their function. However, it has been suggested that IL-6 and IL-1β may work in concert or competition when inducing M2 polarization and, importantly, implicate cytokine release, phagocytic activity, and tissue repair processes. In this review, we discuss the recent literature on the participation of IL-6 and IL-1β cytokines in macrophage polarization and how metabolic stress changes cytokine functions and synergistic relations. A better understanding of these cytokines would serve as an important step toward exploring alternative antiviral strategies directed against metabolic disturbance and, hence, approve further endeavors.