The iNOS/Src/FAK axis contributes to lithium chloride-mediated macrophage migration

Area of Science:

• Immunology
• Cell Biology
• Pharmacology

Background:

• Lithium chloride (LiCl) is a mood stabilizer, but its effects on immune cells, particularly macrophages, are not well understood.
• Understanding LiCl's impact on immune cell function is crucial for assessing its broader biological implications beyond mood stabilization.

Purpose of the Study:

• To investigate the biological effects of lithium chloride (LiCl) on macrophage motility and the underlying molecular mechanisms.
• To elucidate the role of specific signaling pathways, including Src family kinases (SFKs) and focal adhesion kinase (FAK), in LiCl-induced macrophage responses.

Main Methods:

• Stimulation of RAW264.7 and primary murine peritoneal macrophages (PEMs) with LiCl.
• Assessment of cell motility and protein tyrosine phosphorylation.
• Inhibition studies using PP2 (SFK inhibitor), Src knockdown, iNOS-null macrophages, and FAK knockdown.
• Analysis of NF-kB activation and expression of Src, Lyn, Fgr, and Hck.
• Treatment with other GSK3β inhibitors (SB216763, Kenpaullone) to confirm pathway involvement.

Main Results:

• LiCl significantly increased macrophage motility and protein tyrosine phosphorylation.
• Src family kinases (SFKs), particularly Src, and focal adhesion kinase (FAK) were identified as key mediators of LiCl-induced migration.
• The nitric oxide synthase (iNOS)/Src/FAK signaling axis was found to be critical for LiCl-stimulated macrophage locomotion.
• Inhibition of glycogen synthase kinase 3 beta (GSK3β) by LiCl and other inhibitors led to increased iNOS, Src, FAK phosphorylation, and migration.

Conclusions:

• Lithium chloride promotes macrophage migration via the iNOS/Src/FAK signaling pathway, mediated by GSK3β inhibition.
• This study reveals a novel mechanism by which LiCl influences immune cell function, highlighting its potential impact on inflammatory and immune responses.