Triggering receptor expressed on myeloid cells 1 (TREM-1)-expressing intestinal macrophages are significantly increased in the colons of patients with
inflammatory bowel disease (IBD). We focused here on the effects of
guggulsterone on macrophage modulation in
colitis as a potential therapeutic molecule in human IBD and explore the underlying mechanisms. Gene expression in macrophages was examined and wound-healing assay using HT-29 cells was performed.
Colitis in wild-type and IL-10-,
Toll-like receptor 4 (TLR4)-, and myeloid differentiation primary response 88 (MyD88)-deficient mice was induced via the administration of
2,4,6-trinitrobenzene sulfonic acid (TNBS) into the colon. In both in vitro and in vivo experiments,
guggulsterone suppressed intestinal
inflammation amplified by TREM-1 stimulation, in which the suppression of NF-κB, activating protein-1, and
proteasome pathways was involved. In the TNBS-induced
colitis model,
guggulsterone reduced disease activity index scores and TREM-1 expression, stimulated
IL-10 production, and improved survival in wild-type mice. These effects were not observed in IL-10-, TLR4-, and MyD88-deficient mice.
Guggulsterone also suppressed M1 polarization, yet induced the M2 phenotype in macrophages from IBD patients as well as from mice. These findings indicate that
guggulsterone blocks the hyperactivation of macrophages via TREM-1 suppression and induces M2 polarization via
IL-10 mediated by the TLR4 signaling pathway. Furthermore, this study provides a new rationale for the therapeutic potential of
guggulsterone in the treatment of IBD. NEW & NOTEWORTHY We found that
guggulsterone attenuates
triggering receptor expressed on myeloid cells 1 (TREM-1)-mediated hyperactivation of macrophages and polarizes macrophages toward the M2 phenotype. This was mediated by
IL-10 and partly
Toll-like receptor 4 signaling pathways. Overall, these data support that
guggulsterone as a natural
plant sterol modulates macrophage phenotypes in
colitis, which may be of novel therapeutic importance in
inflammatory bowel disease treatment.