Guggulsterone ameliorates colitis by suppressing triggering receptor expressed on myeloid cells 1 hyperactivation and modulating macrophage phenotypes

Abstract

Macrophages play an important role in gut homeostasis and intestinal inflammation, where triggering receptor expressed on myeloid cells 1 (TREM-1) is upregulated by proinflammatory cytokines. Indeed, TREM-1-expressing intestinal macrophages are significantly increased in the colons of patients with inflammatory bowel disease (IBD) and amplify intestinal inflammation in experimental colitis. To explore the underlying mechanisms of guggulsterone (GGS), a plant sterol, the effects of guggulsterone on macrophage modulation as a potential therapeutic modecules in IBD were focused on. Guggulsterone suppressed inflammation amplified by TREM-1 stimulation both in vitro and in vivo, in which suppression of NF-κB, AP-1, and proteasome pathway were involved. Guggulsterone reduced the disease activity index and TREM-1 expression, while guggulsterone induced M2 markers in 2,4,6-trinitrobenzene sulfonic acid-induced colitis model and improved survival rate in wild type mice. Interestingly, these effects disappeared in interleukin 10 (IL-10)-, toll-like receptor 4 (TLR4)-, and myeloid differentiation marker 88 (MyD88)-deficient mice. Guggulsterone also suppressed M1 polarization, but induced the M2 phenotype in macrophages from inflammatory bowel disease patients, as well as from mice, in which IL-10 was indispensable. These findings show that guggulsterone blocks the hyperactivation of macrophages via TREM-1 suppression and modulates macrophage phenotype by IL-10 signal pathway activation, which provides a rationale for its therapeutic potential in the treatment of IBD.