• 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.