Abstract
Macrophage polarization plays essential and diverse roles in most diseases, such as atherosclerosis, adipose tissue inflammation, and insulin resistance. Homeostasis dysfunction in M1/M2 macrophage polarization causes pathological conditions and inflammation. Neuroinflammation is characterized by microglial activation and the concomitant production of pro-inflammatory cytokines, leading to numerous neurodegenerative diseases and psychiatric disorders. Decreased neuroinflammation can be obtained by using natural compounds, including flavonoids, which are known to ameliorate inflammatory responses. Among flavonoids, quercetin possesses multiple pharmacological applications and regulates several biological activities. In the present study, we found that quercetin effectively inhibited the expression of lipocalin-2 in both macrophages and microglial cells stimulated by lipopolysaccharides (LPS). The production of nitric oxide (NO) and expression levels of the pro-inflammatory cytokines, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, were also attenuated by quercetin treatment. Our results also showed that quercetin significantly reduced the expression levels of the M1 markers, such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β, in the macrophages and microglia. The M1 polarization-associated chemokines, C–C motif chemokine ligand (CCL)-2 and C-X-C motif chemokine ligand (CXCL)-10, were also effectively reduced by the quercetin treatment. In addition, quercetin markedly reduced the production of various reactive oxygen species (ROS) in the microglia. The microglial phagocytic ability induced by the LPS was also effectively reduced by the quercetin treatment. Importantly, the quercetin increased the expression levels of the M2 marker, IL-10, and the endogenous antioxidants, heme oxygenase (HO)-1, glutamate-cysteine ligase catalytic subunit (GCLC), glutamate-cysteine ligase modifier subunit (GCLM), and NAD(P)H quinone oxidoreductase-1 (NQO1). The enhancement of the M2 markers and endogenous antioxidants by quercetin was activated by the AMP-activated protein kinase (AMPK) and Akt signaling pathways. Together, our study reported that the quercetin inhibited the effects of M1 polarization, including neuroinflammatory responses, ROS production, and phagocytosis. Moreover, the quercetin enhanced the M2 macrophage polarization and endogenous antioxidant expression in both macrophages and microglia. Our findings provide valuable information that quercetin may act as a potential drug for the treatment of diseases related to inflammatory disorders in the central nervous system.
Highlights
Macrophages have been categorized into at least two main polarization phenotypes: M1-polarized macrophages and M2-activated macrophages [1]
The mouse macrophage (RAW26.7) and adult mouse microglial (IMG) cells were used to study the anti-neuroinflammatory mechanisms of quercetin
Our findings indicate that treatment with quercetin effectively reduces the M1 inflammatory responses that stimulate nitric oxide (NO) production, proinflammatory cytokine expression, and lipocalin-2 production in both macrophages and microglial cells
Summary
Macrophages have been categorized into at least two main polarization phenotypes: M1-polarized macrophages and M2-activated macrophages [1]. The activation of M2-polarized macrophages produces neurotrophic factors [3] and secretes anti-inflammatory cytokines, such as interleukin (IL)-10, which leads to anti-inflammatory effects [4,5]. M2-macrophage polarization plays a central role in infection by limiting the immune response to pathogens, thereby preventing damage to the host [6]. Chemokines, C–C motif chemokine ligand (CCL)-2 [7] and C-X-C motif chemokine ligand (CXCL)-10 [8], have been reported to be associated with Th1 immune responses. A recent report found that the induction of CCL2 and CXCL10 secretions in macrophages exaggerated the host-derived immune responses [9]. The heterogeneity of macrophage polarization plays a critical role in several diseases, such as atherosclerosis [10], pulmonary infection [11], and obesity-associated metabolic diseases [12].
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