Natural Compounds Regulate Macrophage Polarization and Alleviate Inflammation Against ALI/ARDS

Abstract

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a pulmonary disease with high mortality associated with inflammation. During the development of ALI/ARDS, macrophages usually polarize toward M1 pro-inflammatory macrophages, promoting the inflammatory response in ALI/ARDS and aggravating lung tissue damage. Natural compounds with anti-inflammatory activity have achieved excellent results in the treatment of ALI/ARDS through different regulatory modes, including macrophage polarization. Of note, flavonoid, brevilin A, and tetrahydropalmatine play an important role in the treatment of ALI/ARDS by modulating the phenotypic polarization of macrophages and their pro-inflammatory cytokine expression in innate immune cells of the lung. Flavonoids are a kind of naturally occurring polyphenol compound, which has antioxidant and anti-inflammatory activities. Studies have found that some flavonoids can alleviate ALI/ARDS through inhibiting the expression of inflammatory cytokines in macrophages. Among them, 5-methoxyflavone, acacetin, grape seed proanthocyanidins, and luteolin can also regulate macrophage polarization. Therefore, the in-depth exploration of the regulatory mechanism of macrophages can lay the foundation for the application of flavonoids in alleviating inflammation-related lung injury. This review focuses on the macrophage polarization effects of different natural compounds and their potential anti-inflammatory mechanisms in the treatment of ALI/ARDS.

Keywords: acute lung injury/acute respiratory distress syndrome; flavonoid; inflammation; macrophage polarization; natural compound.

Figure 1

Regulatory mechanism of flavonoids on macrophages in LPS stimulation. (A–C) Naringin, myricetin, and hydnocarpin D attenuate the activation of the NF-κB and MAPK signal pathways by inhibiting the degradation of IκBα, nuclear translocation of NF-κB p65, and phosphorylation of ERK, JNK, and p38 in macrophages, thus blocking the expression of inflammatory factors in macrophages. (D) Acacetin can inhibit the TRAF6/NF-κB/COX-2 signal pathway. (E) The activation of TREM2 by binding to grape seed proanthocyanidin can promote the phosphorylation of the PI3K/Akt signal pathway downstream and regulate the polarization of macrophages from M1 to M2. Akt: protein kinase B; COX-2: cyclooxygenase-2; ERK: extracellular signal-regulated kinase; Ikkα/β: nuclear factor κB kinase α/β; IκB: inhibitor of NF-κB; JNK: c-Jun N-terminal kinases; MAPK: mitogen-activated protein kinase; MyD88: myeloid differentiation factor-88; NF-κB: nuclear factor-κB; PI3K: phosphoinositide 3-kinase; TRAF: TNF receptor-associated factor; TLR4: toll-like receptor 4; TRAF6: TNF receptor-associated factor 6; TREM2: triggering receptor expressed on myeloid cells 2.

Figure 2

Effects of hydnocarpin D and 5-methoxyflavone on macrophages in LPS stimulation. (A,B) Hydnocarpin D can increase the expression of antioxidant factors Nrf2 and HO-1 and reduce the expression of its negative regulatory factor Keap1, thus inhibiting the inflammatory response and oxidative stress caused by macrophages. 5-Methoxyflavone inhibits the activation of STAT1 signal by activating the Nrf2/HO-1 signal pathway in macrophages and, finally, reverses the polarization of M1 macrophages and the repolarization of M2 macrophages to M1. HO-1: heme oxygenase-1; Keap1: kelch-like ECH-associated protein 1; Nrf2: nuclear factor erythroid 2-related factor 2; ROS: reactive oxygen species; STAT1: signal transducer and activator of transcription-1.