Glutaredoxin 1 regulates macrophage polarization through mediating glutathionylation of STAT1

Abstract

Background: Macrophage polarization affects tumor growth, metabolism, and many other tumor processes. M1 macrophages can promote antitumor immunity response. Signal transducer and activator of transcription 1 (STAT1) is one of the critical transcription factors in this process, which promotes the expression of a series of inflammatory molecules. STAT1 has been reported as a potential target of reactive oxygen species (ROS)-induced glutathionylation, while the glutathionylation of STAT1 in macrophages and its underlying regulatory mechanism remains unclear. Glutaredoxin 1 (Grx1) functions as a deglutathionylation enzyme, which regulates the activities of many proteins through reversing glutathionylation. Methods: GeneChip and RT-qPCR was first applied to test the mRNA level of Grx1 in M1 macrophages. Western blot was then used to evaluate the variations of the Grx1 protein expression in M1 macrophages. Next, immunoprecipitation was used to investigate the glutathionylated STAT1 in both wild-type and Grx1 −/− mouse macrophages. Finally, the induced alterations of STAT1 activity and function by Grx1 in M1 macrophage were examined by western blot and RT-qPCR. Results: In M1-type macrophages, the levels of Grx1 were elevated. Glutathionylation of STAT1 was negatively regulated by Grx1. Furthermore, depletion of Grx1 increased the activity of STAT1, and thereby promoted the mRNA level of C-X-C motif chemokine ligand 9 (CXCL9) during M1-type polarization of macrophages. Conclusions: Grx1 controlled deglutathionylation of STAT1, which in turn might regulate M1-type polarization of macrophages.

Extracellular Vesicle/Macrophage Axis: Potential Targets for Inflammatory Disease Intervention

“…However, STAT1 is different from STAT6. When JAK1 is activated, it induces the activation of STAT1 in a similar manner, thereby promoting the activation of M1-like macrophages and promoting the aggravation of the inflammatory response ( 125 ). EV-miR-221 secreted by mammary epithelial cells in mastitis and cardiac-derived EV-miR-155-5p in myocardial ischemia-reperfusion injury can induce STAT1 activation and induce M1-like macrophage polarization to aggravate the disease.…”

Topical Administration of 0.3% Tofacitinib Suppresses M1 Macrophage Polarization and Allograft Corneal Rejection by Blocking STAT1 Activation in the Rat Cornea

“… 18 , 19 Pharmacological inhibition of JAK/STAT1 signaling can repress M1 macrophage polarization. 20 , 21 Tofacitinib is a pan-JAK inhibitor that can preferentially inhibit the JAK/STAT1 pathway. 22 , 23 In this study, we explored the effects of tofacitinib on corneal lymphangiogenesis and CGR via the inhibition of M1 macrophage polarization.…”

Macrophage Polarization and Reprogramming in Acute Inflammation: A Redox Perspective

“…In their work, ROS induce S-glutathionylation of fatty acid binding protein (FABP5) in macrophages, which increases nuclear FABP5 levels, activates PPARβ/δ, and abrogates inflammation in the macrophages incubated with LPS [ 172 ]. Therefore, if we bear in mind that the GRX1 levels in the M1-type macrophages were high [ 173 ], the use of different specific inhibitors of GRX1, such as CWR-J02 or APR-246/MQ, to modulate the macrophage polarization process during inflammation would appear to be a promising therapeutic strategy [ 171 , 174 ]. Strikingly, the administration of GRX2, an isoform that, unlike GRX1, is not inhibited by the oxidation of structural Cys residues [ 175 ], lowers NO levels in macrophages and alleviates asthma-like acute airway inflammation in mice [ 176 ].…”