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Abstract
Post-translational redox modification of methionine residues often triggers a change in protein function. Emerging evidence points to this reversible protein modification being an important regulatory mechanism under various physiological conditions. Reduction of oxidized methionine residues is catalyzed by methionine sulfoxide reductases (Msrs). Here, we show that one of these enzymes, a selenium-containing MsrB1, is highly expressed in immune-activated macrophages and contributes to shaping cellular and organismal immune responses. In particular, lipopolysaccharide (LPS) induces expression of MsrB1, but not other Msrs. Genetic ablation of MsrB1 did not preclude LPS-induced intracellular signaling in macrophages, but resulted in attenuated induction of anti-inflammatory cytokines, such as interleukin (IL)-10 and the IL-1 receptor antagonist. This anomaly was associated with excessive pro-inflammatory cytokine production as well as an increase in acute tissue inflammation in mice. Together, our findings suggest that MsrB1 controls immune responses by promoting anti-inflammatory cytokine expression in macrophages. MsrB1-dependent reduction of oxidized methionine in proteins may be a heretofore unrecognized regulatory event underlying immunity and inflammatory disease, and a novel target for clinical applications.
Highlights
Methionine sulfoxide reductase (Msr) plays a critical role in redox regulation of proteins; it reduces methionine sulfoxide residue, a product of methionine oxidation, converting it back to methionine
Whereas MSRA, MSRB1, and MSRB2 were ubiquitously expressed in all cell lines in the dataset, dramatic increases in MSRB1 expression were observed in some immune cell types
MSRB1 expression in BMDMs was potently induced over the course of the LPS response, whereas the expression of other Msr forms was decreased or remained unchanged upon LPS treatment
Summary
Methionine sulfoxide reductase (Msr) plays a critical role in redox regulation of proteins; it reduces methionine sulfoxide residue, a product of methionine oxidation, converting it back to methionine. Macrophages serve a variety of physiological functions, such as orchestrating innate and adaptive immune responses, clearing cell debris, and coordinating tissue development and homeostasis[14, 15] While engaged in these processes, macrophages produce a multitude of cytokines in response to stimulation by molecules associated with tissue damage and microbial infection. In a properly functioning immune system, the production of proand anti-inflammatory cytokines is subject to tight control; its balance is crucial for ensuring optimal immune defense and tissue maintenance as well as avoiding excessive and self-destructive inflammatory reactions It remains incompletely understood how macrophages interpret their physiological state and external stimuli from the environment, and integrate this complex information into biochemical mechanisms governing cytokine gene expression[14]. Our findings revealed a role for MsrB1 in anti-inflammatory cytokine gene expression in macrophages and the control of acute inflammation in vivo
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