IIIM-941, a Stilbene Derivative Inhibits NLRP3 Inflammasome Activation by Inducing Autophagy
| Autor: | Mehboob Ali, Mehak Gupta, Abubakar Wani, Ankita Sharma, Mohd Abdullaha, Dilpreet Kour, Sushil Choudhary, Sandip B. Bharate, Gurdarshan Singh, Ajay Kumar |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
autophagy AMP kinase Inflammation RM1-950 ASC oligomerization Inhibitory postsynaptic potential 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Pharmacology (medical) Original Research CAMKK2 Pharmacology integumentary system Autophagy Bafilomycin AMPK Inflammasome calcium/calmodulin-dependent kinase kinase 2 NLRP3 inflammasome Cell biology 030104 developmental biology chemistry inflammation Therapeutics. Pharmacology NLRP3 inflammasome activation medicine.symptom 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Frontiers in Pharmacology Frontiers in Pharmacology, Vol 12 (2021) |
| ISSN: | 1663-9812 |
| Popis: | Aberrant activation of NLRP3 inflammasome has been implicated in several inflammatory diseases. Autophagy is one of the primary mechanisms that regulate the NLRP3 inflammasome. In this study, we attempted to target NLRP3 inflammasome activity by a synthetic compound IIIM-941. We found that IIIM-941 inhibits ATP-induced NLRP3 inflammasome by induction of autophagy through the AMPK pathway in bone marrow-derived macrophages (BMDMs) and J774A.1 cells. It was interesting to observe that IIIM-941 did not show any inhibitory activity against LPS induced pro-inflammatory cytokines TNF-α and IL-6. The anti-NLRP3 activity of IIIM-941 was considerably reversed when we attempted to block autophagy by using either pharmacological inhibitor bafilomycin A1or by using siRNA against AMPK. Further, we found that IIIM-941 downregulated the expression of NLRP3 and prevented the oligomerization of ASC to exert its anti-NLRP3 inflammasome effect in J774A.1 cells. We validated the inhibitory activity of IIIM-941 against NLRP3 inflammasome in three different mice models. The anti-inflammatory effect of IIIM-941 was highly significant in the ATP-induced peritoneal inflammation model. While IIIM-941 was similarly effective in suppressing MSU-induced IL-1β in the air pouch model of inflammation without affecting the levels of TNF-α and IL-6. Finally, oral efficacy of IIIM-941 was also proved in the MSU-induced foot paw edema model of inflammation in mice at 10 and 20 mg/kg (b.w.). The compounds like IIIM-941 can be explored further for the development of therapies against diseases such as Alzheimer’s disease and Parkinson’s disease, where hampered autophagy and NLRP3 activation play a crucial role in pathological development. |
| Databáze: | OpenAIRE |
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