Indole-3-propionic acid alleviates chondrocytes inflammation and osteoarthritis via the AhR/NF-κB axis

Abstract

Background Osteoarthritis (OA) is a common chronic disease characterized by chronic inflammation and extracellular matrix degradation. Indole-3-propionic acid (IPA) is a tryptophan metabolite secreted by intestinal flora, which can exert anti-inflammatory effects in a variety of diseases. In this study, we further investigated the potential therapeutic role of IPA in OA and the underlying mechanism. Methods IL-1β was utilized to induce chondrocyte inflammation. Then, the cytotoxicity of IPA on rat chondrocytes was assessed. Meanwhile, RT-qPCR, Griess reaction, ELISA, Western blot and immunofluorescence were performed to evaluate the expression of inflammatory factors and stromal proteins, and the NF-κB pathway in chondrocytes treated with IL-1β alone, with IPA or with aryl hydrocarbon receptor (AhR) knockdown. An OA rat model was established by anterior cruciate ligament transection, and hematoxylin-eosin staining, Safranin-O/Fast Green staining and immunochemistry were applied to estimate OA severity. Results IPA did not affect cellular viability at concentrations up to 80 µM. IPA significantly inhibited the IL-1β-induced expression of inflammatory factors (Nitric oxide, PGE2, TNF-α, IL-6, iNOS and COX-2) and matrix-degrading enzymes (MMP-3, MMP-13 and ADAMTS-5), upregulated the expression of anabolic markers (aggrecan and collagen-II) and inactivated the NF-κB pathway. However, AhR knockdown could abolish the above protection capabilities and the suppression of the NF-κB pathway induced by IPA. Furthermore, IPA significantly reduced serum inflammatory cytokines expression, cartilage destruction and synovitis in vivo, demonstrating its protective role in OA progression. Conclusion IPA improved IL-1β-induced chondrocyte inflammation and extracellular matrix degradation through the AhR/NF-κB axis, which provides an innovative therapeutic strategy for OA.

Indole-3-Propionic Acid Protects Against Heart Failure With Preserved Ejection Fraction

“…In regard to the downregulation of cardiac NNMT by IPA, it has been reported that the proinflammatory cytokines, such as IL-6 and TNF-a, elicit significant induction of NNMT expression. 37 Since IPA has whole-body anti-inflammatory effects in multiple disease models, 23,29,38,39 we examined whether IPA could downregulate cardiac NNMT through an anti-inflammatory response. The expression of proinflammatory cytokine TNF-α is increased in the mice heart upon HFpEF diet feeding and IPA supplementation decreased TNF-α expression, in accordance with the expression of NNMT (Figure 4I and 4J).…”

ADAMTS5 Promotes Permeability of the Blood-Brain Barrier during Treponema pallidum Subspecies pallidum Invading the Central Nervous System

“…Given the documented ability of IL-1β to induce ADAMTS5 up-regulation in human chondrocytes, , we determined the expression level of IL-1β in Tp-treated hCMEC/D3 cells. After stimulation with Tp at an MOI of 50:1 for 24 h, the expression of IL-1β was detected by RT-qPCR and ELISA.…”

“…Considering that IL-1β had been demonstrated to induce the up-regulation of ADAMTS5 in human chondrocytes, , we also investigated whether Tp regulated the expression of ADAMTS5 through IL-1β. Our findings revealed that Tp induced the production of IL-1β in hCMEC/D3 cells and that recombinant human IL-1β promoted the expression of ADAMTS5 in these cells, which was consistent with previous studies. , Moreover, the inhibition of IL-1β using diacerein significantly reduced the production of ADAMTS5.…”

“…Considering that IL-1β had been demonstrated to induce the up-regulation of ADAMTS5 in human chondrocytes, , we also investigated whether Tp regulated the expression of ADAMTS5 through IL-1β. Our findings revealed that Tp induced the production of IL-1β in hCMEC/D3 cells and that recombinant human IL-1β promoted the expression of ADAMTS5 in these cells, which was consistent with previous studies. , Moreover, the inhibition of IL-1β using diacerein significantly reduced the production of ADAMTS5. These data suggested that Tp enhanced ADAMTS5 expression by inducing the production of IL-1β, and IL-1β could regulate the expression of ADAMTS5, which might indirectly affect the subsequent effects of ADAMTS5.…”

“…ADAMTS5, a secreted metalloprotease, was known for its capacity to degrade aggrecan . Since its discovery in 1999, extensive research had focused primarily on conditions such as osteoarthritis and joint degeneration. − Notably, it had been observed that interleukin-1β (IL-1β) could up-regulate the expression of ADAMTS5 in human chondrocytes. , A deeper understanding of ADAMTS5 revealed its involvement in the degradation of a critical structural component of the vascular endothelium’s extracellular matrix, known as the endothelial glycocalyx . The endothelial glycocalyx was an extracellular matrix layer that covered the surface of endothelial cells, primarily composed of heparan sulfate, chondroitin sulfate, and hyaluronic acid .…”