Blockage of Kv1.3 regulates macrophage migration in acute liver injury by targeting δ-catenin through RhoA signaling

Abstract

Background: Activation of macrophages and infiltration are key events in acute liver injury (ALI). Kv1.3 plays an important role in regulating immunologic functions of macrophages and is extensively recognized as a potential ion channel for immunological diseases. Objective: We hypothesized that blockage of Kv1.3 may influence ALI by inhibiting macrophages infiltration in damaged liver tissues. Methods: Margatoxin was administered into the peritoneal cavity of ALI mice. The impact of this treatment on ALI and macrophage migration in vivo and in vitro was determined using immunohistochemistry, transwell migration, and wound healing assays. Results: MgTX treatment alleviated ALI in mice, as evidenced by reduced macrophage infiltration in liver tissues and lower serum levels of liver ALT and AST. RNA-seq profiling analysis showed that the most obvious change by MgTX treatment was downregulation of δ-catenin, a protein known to be associated with macrophage migration. The effect of MgTX on macrophage migration and involvement of δ-catenin was confirmed by transwell and wound healing assays. Overexpression of δ-catenin in RAW264.7 cells promoted migration, an event that was suppressed upon silencing of δ-catenin. Mechanistically, the expression of RhoA was regulated by the overexpression or knockdown of δ-catenin. Conclusion: These findings suggest a role for blockage of Kv1.3 channel in macrophage migration and reveal a new target in the treatment of ALI.

The voltage-gated potassium channel KV1.3 regulates neutrophil recruitment during inflammation

“…In addition, the calculated extravasation index suggests that K V 1.3 might also be involved in neutrophil transmigration across the inflamed endothelium. This hypothesis is supported by reports revealing that interference with K V 1.3 reduces cell migration in macrophages, 44 , 45 T cells, 40 or microglia cells, 46 too.…”

Promotion of epithelial-mesenchymal transformation by hepatocellular carcinoma-educated macrophages through Wnt2b/β-catenin/c-Myc signaling and reprogramming glycolysis

“…Notably, Tang et al [ 32 ] have recently found that CTNND1(delta-catenin) was highly expressed in HCC tissues and dramatically enhanced Wnt/β-catenin signaling, indicating CTNND1 might act as a regulator of the canonical Wnt/β-catenin signaling pathway [ 33 ]. Although CTNND1 has been shown to be associated with macrophage migration and influence macrophage in the inflammatory response [ 34 , 35 ], whether CTNND1 can promote the M2 polarization through activating canonical Wnt/β-catenin signaling pathway in HCC-TAMs remains to be further explored.…”

KV1.3 channels are novel determinants of macrophage‐dependent endothelial dysfunction in angiotensin II‐induced hypertension in mice

“…Blockade of K V 1.3 channels suppresses antigen-driven proliferation and cytokine production in T cells and macrophages. Therefore, selective K V 1.3 channel blockers ameliorate different pathologies that involve inflammation including multiple sclerosis, autoimmune diabetes and acute liver injury (Beeton et al, 2005;Beeton, Wulff, et al, 2001;Chi et al, 2012;Rus et al, 2005;Wu et al, 2020 (Qian et al, 2014) and 4 weeks (Qi et al, 2019;Ye et al, 2019).…”

“…Blockade of K V 1.3 channels suppresses antigen‐driven proliferation and cytokine production in T cells and macrophages. Therefore, selective K V 1.3 channel blockers ameliorate different pathologies that involve inflammation including multiple sclerosis, autoimmune diabetes and acute liver injury (Beeton et al, 2005; Beeton, Barbaria, et al, 2001; Beeton, Wulff, et al, 2001; Chi et al, 2012; Rus et al, 2005; Wu et al, 2020). Our study demonstrates that K V 1.3 channels are important determinants of macrophage phenotype in AngII‐induced hypertension, which in turn participates in endothelial dysfunction.…”