Imbalance between serum DNase-I protein levels and enzymatic activity in SLE: link with mitochondrial-DNA and low-density granulocytes.

OBJECTIVE

To analyze the role of DNase-I and its main regulatory factors controlling the cirDNA degradation, in relation to LDG subsets in SLE.

METHODS

DNase-I, anti-DNase-I antibodies and plasma gelsolin (pGSN) levels were quantified using immunoassays in SLE patients (n = 144) and controls (n = 42). DNase-I activity and cirDNA concentrations were determined by fluorescence-based assays, while mitochondrial/nuclear DNA (mtDNA/nDNA) was quantified by qPCR and LDGs by flow cytometry.

RESULTS

Serum DNase-I levels were increased in SLE without a concomitant increase in DNase activity, particularly among anti-dsDNApositive patients, who also displayed the highest cirDNA concentrations. Furthermore, anti-DNase-I antibody levels were elevated in these patients and positively correlated with the DNase-I/cirDNA ratio. Upregulation of DNase-I was counteracted by the DNase-regulatory protein pGSN, whose levels were reduced in active patients or with cardiovascular disease. Moreover, higher pGSN levels were associated with fewer CD16neg-LDG, an atherogenic subset. Notably, mtDNA may contribute to the generation of CD16pos-LDG, which were increased in SLE and inversely associated with DNase activity. However, mtDNA in controls correlated with circulating DNase-I levels and activity, suggesting a homeostatic role.

CONCLUSION

The DNase-I levels vs enzymatic activity imbalance in SLE may be influenced by elevated anti-DNase-I antibodies and diminished pGSN concentrations, collectively impairing cirDNA degradation and promoting anti-DNA autoantibody production. Additionally, our findings suggest a homeostatic role for mtDNA in DNase-I regulation, which is disrupted in SLE. Moreover, pGSN appears to exert a protective effect by preserving DNase-I activity and restraining the CD16neg-LDGs expansion, highlighting its potential therapeutic application in SLE-related cardiovascular complications.