Salicylates Ameliorate Intestinal Inflammation by Activating Macrophage AMPK

Abstract

Background Inflammatory bowel diseases are the most common chronic intestinal inflammatory conditions, and their incidence has shown a dramatic increase in recent decades. Limited efficacy and questionable safety profiles with existing therapies suggest the need for better targeting of therapeutic strategies. Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of cellular metabolism and has been implicated in intestinal inflammation. Macrophages execute an important role in the generation of intestinal inflammation. Impaired AMPK in macrophages has been shown to be associated with higher production of proinflammatory cytokines; however, the role of macrophage AMPK in intestinal inflammation and the mechanism by which it regulates inflammation remain to be determined. In this study, we investigated the role of AMPK with a specific focus on macrophages in the pathogenesis of intestinal inflammation. Methods A dextran sodium sulfate-induced colitis model was used to assess the disease activity index, histological scores, macroscopic scores, and myeloperoxidase level. Proinflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and interleukin-1β were measured by enzyme-linked immunosorbent assay. Transient transfection of AMPKβ1 and LC3-II siRNA in RAW 264.7 cells was performed to elucidate the regulation of autophagy by AMPK. The expression of p-AMPK, AMPK, and autophagy markers (eg, LC3-II, p62, Beclin-1, and Atg-12) was analyzed by Western blot. Results Genetic deletion of AMPKβ1 in macrophages upregulated the production of proinflammatory cytokines, aggravated the severity of dextran sodium sulfate-induced colitis in mice, which was associated with an increased nuclear translocation of nuclear factor-κB, and impaired autophagy both in vitro and in vivo. Notably, the commonly used anti-inflammatory 5-aminosalicylic acid (ie, mesalazine) and sodium salicylate ameliorated dextran sodium sulfate-induced colitis through the activation of macrophage AMPK targeting the β1 subunit. Conclusions Together, these data suggest that the development of therapeutic agents targeting AMPKβ1 may be effective in the treatment of intestinal inflammatory conditions including inflammatory bowel disease.

Intestinal Epithelial AMPK Deficiency Causes Delayed Colonic Epithelial Repair in DSS-Induced Colitis

“…These data suggest that targeting immune cells with AMPK activators represents a promising pharmacological tool against bowel inflammation. In support, salicylate, a direct AMPKβ1 activator, has been recently proven to be therapeutically effective in ameliorating inflammation in DSS-induced colitis by the activation of macrophage autophagy through an AMPK-dependent mechanism [ 60 ]. In the present study, to test the therapeutic relevance of IEC AMPK activation, we administrated metformin at the beginning of the recovery phase after withdrawal of DSS to limit the impact of metformin action on the inflammatory phase.…”

Disruption of autophagy by increased 5-HT alters gut microbiota and enhances susceptibility to experimental colitis and Crohn’s disease

“…Autophagy-deficient mice are highly susceptible to experimental colitis and produce more pro inflammatory cytokines (7,8). Studies demonstrate that autophagy-enhancing pharmacological agents such as rapamycin and salicylates (or other mTOR-inhibiting and AMPK-activating drugs) reduce the severity of experimental colitis and refractory CD, suggesting that these substances may promote a protective role of autophagy in gut inflammation (9)(10)(11)(12). However, therapies that inhibit mTOR/enhance autophagy such as rapamycin have many side effects including altered insulin sensitivity, nephrotoxicity, hyperlipidemia, thrombocytopenia, and diminished wound healing (13).…”

Saffron Pre-Treatment Promotes Reduction in Tissue Inflammatory Profiles and Alters Microbiome Composition in Experimental Colitis Mice

“…Cytoplasmic and nuclear proteins were extracted by using the NE-PER nuclear and cytoplasmic extraction reagent kit (no. 78833, Thermo Scientific, Waltham, MA, USA) as described earlier [ 5 ]. Briefly, the protein concentration in the extract was determined by the DC Protein Assay Kit (Bio-Rad Laboratories, Mississauga, ON, Canada).…”

“…The etiology of IBD is complex and various studies suggest that its pathogenesis is associated with a dysregulated immune response, genetic factors, gut microbiota, and environmental factors [ 2 ]. Various immunosuppressive synthetic drugs and biologics, such as salicylates, corticosteroids, tumor necrosis factor (TNF) blockers, and vedolizumab, are available as therapies for IBD, and many additional options are in the pipeline [ 3 , 4 , 5 ]. Clinical data suggest that these therapies are limited in managing the disease in some patients, while some fail to respond over time.…”