The NLRP3 Inflammasome Works as a Sensor for Detecting Hypoactivity of the Mitochondrial Src Family Kinases

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Gefitinib (GF), an epidermal growth factor receptor tyrosine kinase inhibitor (TKI), induces lung inflammation via the NLR family pyrin domain containing 3 (NLRP3) inflammasome.
• The precise molecular targets and mechanisms driving GF-induced inflammation remain unclear.

Purpose of the Study:

• To identify the molecular targets and mechanisms responsible for Gefitinib-induced NLRP3 inflammasome activation.
• To investigate the role of mitochondrial Src family kinases (mSFKs) in TKI-mediated inflammasome activation.

Main Methods:

• Analysis of tyrosine kinase inhibitors (TKIs) for NLRP3 inflammasome activation in human monocytic THP-1 cells and bone marrow-derived macrophages.
• Investigating off-target activities of TKIs against mitochondrial Src family kinases (mSFKs) including c-Src, Fgr, and Fyn.
• Assessing the impact of kinase loss on NLRP3 inflammasome activation in THP-1 cells.

Main Results:

• All tested TKIs are potent NLRP3 inflammasome agonists.
• TKIs exhibit shared off-target activity against mSFKs, crucial for inflammasome activation.
• Loss of specific mSFKs spontaneously activates the NLRP3 inflammasome, indicating a sensing mechanism.

Conclusions:

• Mitochondrial Src family kinases (mSFKs) are key determinants of Gefitinib-induced NLRP3 inflammasome activation.
• The NLRP3 inflammasome likely senses mSFK hypoactivity, which leads to mitochondrial dysfunction.
• This study establishes a mechanistic link between NLRP3 inflammasome and mSFKs, revealing novel insights into inflammasome function.