• Background
Ulcerative colitis (UC) is an autoimmune disease that affects the colon
and rectum. It is characterized by diffuse, superficial, and localized
inflammation of the mucosa[1, 2]. Although the causative factors of
ulcerative colitis are not fully understood, multiple causes have been
identified, including changes in the intestinal flora, genetic
susceptibility, immune response disorders, and environmental factors.
Clinical treatment usually involves 5-aminosalicylic acid,
corticosteroids, thiopurines, and biological agents such as anti-tumor
necrosis factor (TNF)-α antibodies. However, these treatments can cause
specific side effects, including diarrhea, complicated myocarditis, and
hemolytic anemia [3].
Macrophages, which is considered as central mediators of intestinal
immune homeostasis and inflammation, exert pathological influences in
both UC and Crohn’s [4]. Toll-like receptors (TLRs) are activated by
pathogen-associated molecular patterns (PAMPs), which in turn activate
macrophages leading to excessive inflammation and tissue damage, causing
colitis [5]. Moreover, innate immune signaling via cytokine
receptors and TLRs mediated macrophages activation act as a primary
response to promote NOD-like receptor family pyrin domain containing 3
(NLRP3) transcription through NF-kB activation[6].
The NLRP3 inflammasome is a cytosolic protein complex consisting of
NLRP3, apoptosis-associated speck-like protein containing CARD (ASC),
and pro-Caspase1. This complex is present in various immune cells such
as granulocytes, macrophages, and lymphocytes and is crucial for
maintaining gut homeostasis[7]. Toll-like receptors (TLRs) activate
the NLRP3 inflammasome through the adaptor protein MyD88, which leads to
the phosphorylation of the nuclear factor kappa-B (NF-κB), ultimately
triggering downstream inflammation. The NLRP3 inflammasome identifies a
range of signals such as stress, foreign microorganisms, and endogenous
danger signals, producing interleukin-1β (IL-1β) and IL-18, thereby
promoting inflammation [8, 9]. IL-1β plays an important role in the
colon and is mainly derived from macrophages in the lamina propria. It
has various functions such as guiding neutrophils to infected or damaged
sites, enhancing T cell proliferation, promoting phagocytosis to destroy
bacteria, and activating additional pathways to upregulate cytokines,
amongst others [8, 10].
Forsythia suspensa (Thunb.) Vahl is an ornamental shrub and its
fruits were used as a well-known Chinese herbal medicine with
detoxifying and heat-clearing properties. Over the past few decades,
several monomeric compounds with antioxidant, anti-inflammatory,
anti-viral, neuroprotective, and antibacterial effects have been
identified from Forsythia suspensa [11]. One of these
compounds, phillygenin (PHI), is a lignan known to inhibit inflammation,
ameliorate liver fibrosis, inhibit epithelial-mesenchymal transition,
reduce nonalcoholic fatty liver disease, and regulate proliferation and
apoptosis [12-15]. PHI is involved in several pathways including the
SHP-1/JAK2/STAT3, AMPK/ERK/NF-κB, and TLR4/MyD88/NF-κB pathways
[16-18]. However, the impact of PHI on inflammatory bowel disease
remains understudied. In the current study, we performed a detailed
study on the pharmacological impact of PHI on colitis and its mechanism
of action.