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Leukadherin-1 inhibits NLRP3 inflammasome by blocking inflammasome assembly

Aberrant activation of the NLRP3 inflammasome has been implicated in the occurrence and development of many inflammatory diseases, and thus potent inhibitors of the NLRP3 inflammasome should be explored. An antitumor agent, Leukadherin-1 (LA-1), tested in phase 1/2 clinical trials, has been reported to exert anti-inflammatory properties by blocking the NF-κB pathway. However, the effects of LA-1 on the NLRP3 inflammasome have not been conclusively determined. In this study, we found that at lower doses (below 1 μM) ex vivo, LA-1 blocked NLRP3 inflammasome activation without affecting NF-κB signaling. Accordingly, 1 mg/Kg LA-1 strongly inhibited the release of NLRP3-dependent cytokine, but only slightly inhibited NLRP3-independent-cytokines secretion in endotoxemia and alleviated NLRP3-dependent peritonitis in vivo. Mechanistically, LA-1 had no effects on ion flux or mitochondrial injury. Instead, it inhibited NLRP3 inflammasome assembly by suppressing ASC oligomerization, blocking NLRP3 self-assembly, and reducing interactions of NLRP3 with ASC and NEK7. Therefore, LA-1 inhibits NLRP3 inflammasome activation, implying that it is a potential treatment option for NLRP3-associated diseases.

 

Comments:

That's fascinating! It seems like the study has discovered promising aspects of Leukadherin-1 (LA-1) in inhibiting NLRP3 inflammasome activation, which could have significant implications for treating inflammatory diseases linked to this pathway.

LA-1's ability to selectively block NLRP3 inflammasome activation without interfering with the NF-κB pathway at lower doses is intriguing. The in vivo results showcasing its efficacy in reducing NLRP3-dependent cytokine release and alleviating NLRP3-associated peritonitis further underscore its potential as a treatment option for these conditions.

The mechanistic insights revealing how LA-1 affects the NLRP3 inflammasome assembly by suppressing ASC oligomerization, inhibiting NLRP3 self-assembly, and reducing interactions with ASC and NEK7 provide a clearer understanding of its mode of action.

This study's findings could pave the way for exploring LA-1 as a targeted therapeutic approach for NLRP3-associated inflammatory diseases, potentially offering a new avenue for treatment where existing options might be limited.

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S8306 Leukadherin-1 Leukadherin-1 (LA1) is a small molecule agonist that enhances CD11b/CD18-dependent cell adhesion to its ligand ICAM-1(an agonist for the complement receptor 3 (CD11b/CD18)).

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