Year: 2024
Type: editorial
Abstract: In this issue of Circulation Research, He et al. 1 demonstrate a previously undefined role for the cysteine protease Legumain (LGMN) in CD4 + helper T cells, and specifically regulatory T cells (Tregs), in the pathogenesis of hypertension.LGMN, also known as asparaginyl endopeptidase, is an endosomal and lysosomal cysteine protease that cleaves asparagine residues of proteins such as matrix metalloproteinases, cathepsins, and fibronectin.2 He et al. demonstrate increased LGMN levels in CD4 + T cells of hypertensive mice and untreated hypertensive humans.To test causal roles for LGMN, the authors genetically deleted LGMN in CD4 + T cells of mice resulting in reduced BP elevations and aortic and renal fibrosis in response to angiotensin II (Ang II) infusion.These findings were recapitulated with systemic pharmacological inhibition of LGMN using the RR-11a compound.The authors then depleted Tregs in mice with CD4 + T cell LGMN deficiency.This abrogated the blunted hypertensive responses in these mice, suggesting a key role for LGMN in Tregs.To further test a role for LGMN in Tregs, authors generated mice with LGMN deficiency specifically in Tregs.LGMN-deficient Tregs exhibited greater immunosuppressive function and higher levels of the mediator of Treg differentiation and maintenance forkhead box protein 3 (FOXP3) in vitro.In vivo, Treg LGMN deficient mice exhibited reduced BP and end-organ damage as well as decreased inflammatory cytokine production after Ang II infusion.These findings are consistent with a role for LGMN to limit Treg immunosuppressive function and hypertension development.In additional mechanistic studies He et al. 1 demonstrated that LGMN promotes TRAF6 degradation via chaperone-mediated autophagy.Consistent with prior evidence that TRAF6 promotes NFκB activation to induce FOXP3 expression, 3 the loss of TRAF6 resulted in decreased binding of NFκB subunits to the FOXP3 promoter and decreased FOXP3 expression in Tregs.Knockdown of TRAF6 blunted the protective effects of LGMNdeficient Tregs after adoptive transfer to hypertensive mice, implicating TRAF6 degradation in LGMN-mediated Treg dysfunction. 1 Taken together, findings by He et al.
Source: Circulation Research
Authors: Matthew R. Alexander, David G. Harrison
Institutions: Vanderbilt University, Vanderbilt University Medical Center
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4390578115