Key role of the CSE/transsulfuration pathway in macrophage phenotypic change under iron overload

Abstract

Background: Iron homeostasis has a significant impact on the phenotypic transformation of macrophages and is implicated in various diseases. In this study, we evaluated the effect of cystathionine-gamma-lyase (CSE)/transsulfuration pathway in iron-overload induced macrophage phenotype change.

Methods: The biochemical parameters, such as qRT-PCR, western blot, fluorescence staining, were assessed both in vitro and in vivo.

Results: Iron overload disrupts iron metabolism and alters the expression of genes involved in iron transport, resulting in the polarization of macrophages towards the M1 phenotype and an alternating activation state of M2. Meanwhile, excessive iron led to an increase in lipid peroxidation levels and disrupted cysteine metabolism. By utilizing erastin to inhibit SLC7A11 activity and block exogenous cysteine uptake, we were able to observe the exacerbation of the proinflammatory state in macrophages under conditions of cysteine deprivation. The CSE/transsulfuration pathway, serves as the primary route for endogenous cysteine synthesis. In the presence of iron overload, the expression of CSE was upregulated and further enhanced by cysteine deprivation. Deletion of CSE in CSE-knockout mice exacerbated the inflammatory transition of iron-overloaded macrophages by impacting cysteine metabolism and ferritinophagy.

Conclusion: The CSE/transsulfuration pathway regulated macrophage phenotype change under iron-overload, which may offer novel insights into potential therapeutic strategies for iron overload-related disorders.

Keywords: Cystathionine-gamma-lyase; Cysteine; Iron; Macrophage; Transsulfuration pathway.