Neorogioltriol and Related Diterpenes from the Red Alga Laurencia Inhibit Inflammatory Bowel Disease in Mice by Suppressing M1 and Promoting M2-Like Macrophage Responses

Abstract

Macrophages are central mediators of inflammation, orchestrating the inflammatory response through the production of cytokines and nitric oxide. Macrophages obtain pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes, which can be modulated by soluble factors, including natural products. Despite the crucial protective role of inflammation, chronic or deregulated inflammation can lead to pathological states, such as autoimmune diseases, metabolic disorders, cardiovascular diseases, and cancer. In this case, we studied the anti-inflammatory activity of neorogioltriol (1) in depth and identified two structurally related diterpenes, neorogioldiol (2), and O11,15-cyclo-14-bromo-14,15-dihydrorogiol-3,11-diol (3), with equally potent activity. We investigated the mechanism of action of metabolites 1–3 and found that all three suppressed macrophage activation and promoted an M2-like anti-inflammatory phenotype by inducing expression of Arginase1, MRC1, IRAK-M, the transcription factor C/EBPβ, and the miRNA miR-146a. In addition, they suppressed iNOS induction and nitric oxide production. Importantly, treatment of mice with 2 or 3 suppressed DSS-induced colitis by reducing tissue damage and pro-inflammatory cytokine production. Thus, all these three diterpenes are promising lead molecules for the development of anti-inflammatory agents targeting macrophage polarization mechanisms.

Analysis of interleukin-1 receptor associated kinase-3 (IRAK3) function in modulating expression of inflammatory markers in cell culture models: A systematic review and meta-analysis

“…IRAK3 mRNA and protein expression and its effects on inflammation have been studied widely using various experimental models including cell lines [ 10 , 13 , 21 – 24 ], human or mouse primary cells [ 25 – 28 ], and animal in vivo models [ 29 – 31 ], and reported to have contradicting effects on immune responses. Wesche et al .…”

TRAF3 promotes ROS production and pyroptosis by targeting ULK1 ubiquitination in macrophages

“…In response to pathogen infection, inflammatory reactions are activated through recognizing pathogens by pattern recognition receptors (PPRs) in macrophages, such as toll‐like receptors (TLRs). Disordered inflammatory response is known to be one of the most important causes of autoimmune diseases, such as inflammatory bowel diseases, 1,2 systemic sclerosis, 3 polymyositis, 4 and diabetes 5 . Thus, defining the mechanisms of inflammation regulation is then considered of great importance.…”

MiR-98-5p expression inhibits polarization of macrophages to an M2 phenotype by targeting Trib1 in inflammatory bowel disease

“…According to the functional characteristics, macrophages are mainly divided into pro-inflammatory macrophages (M1 polarized phenotype) and anti-inflammatory macrophages (M2 polarized phenotype). Previous studies found that macrophages are closely related to the development of IBD (Rubio & Schmidt, 2018;Leonardi et al, 2018;Fries et al, 2013), and it was confirmed that IBD can be alleviated by inhibiting M1 macrophage polarization and promoting M2 macrophage polarization (Daskalaki et al, 2019). Therefore, investigating the molecules that can affect macrophage polarization may provide new targets for IBD therapy.…”