Dysregulated neutrophils have a pathogenic role in systemic lupus erythematosus (SLE), in particular through the release of neutrophil extracellular traps (NETs) and the subsequent production of type I interferon. However, exactly how neutrophils become dysregulated in SLE is an active area of research.

Credit: Nicholas Mayeux/Stocktrek Images

“Our group had previously identified a pro-inflammatory neutrophil subset known as low-density granulocytes (LDGs). We found that these cells could damage blood vessels and promote immune dysregulation in SLE,” explains Mariana Kaplan, corresponding author of a new study on LDGs.

Little was previously known about the heterogeneity of LDGs and whether subsets existed with distinct pathogenic functions. To address these uncertainties, Kaplan and colleagues used a range of transcriptomic and epigenomic approaches to characterize LDGs from patients with SLE. Notably, they identified two subsets that seemed to represent different stages of LDG maturation and that could be distinguished by their expression of CD10 — CD10− immature LDGs and CD10+ intermediate-mature LDGs.

The researchers went on to functionally characterize these subsets by examining their ability to perform typical neutrophil tasks such as degranulation, NET production and phagocytosis. “Overall, we found that the intermediate-mature subpopulation of LDGs displayed the bulk of the pathogenic features of LDGs and was responsible for the type I interferon gene signature in SLE,” says Kaplan.

Interestingly, high numbers of intermediate-mature LDGs in the blood of patients with SLE correlated with more severe organ damage, reduced kidney function and an increased coronary plaque burden. The results of further in vivo and in vitro studies also suggested a role for these cells in vascular damage.

intermediate-mature LDGs in the blood of patients with SLE correlated with more severe organ damage

“Future studies will focus on identifying potential therapies that can specifically target the intermediate-mature LDG subset in the treatment and/or prevention of lupus vasculopathy and premature cardiovascular disease in SLE,” states Kaplan.