Increased inflammatory low-density neutrophils in severe obesity and effect of bariatric surgery: Results from case-control and prospective cohort studies.

BACKGROUND: Low-density neutrophils (LDN) are increased in several inflammatory diseases and may also play a role in the low-grade chronic inflammation associated with obesity. Here we explored their role in obesity, determined their gene signatures, and assessed the effect of bariatric surgery. METHODS: We compared the number, function, and gene expression profiles of circulating LDN in morbidly obese patients (MOP, n=27; body mass index (BMI) > 40 Kg/m2) and normal-weight controls (NWC, n=20; BMI < 25 Kg/m2) in a case-control study. Additionally, in a prospective longitudinal study, we measured changes in the frequency of LDN after bariatric surgery (n=36) and tested for associations with metabolic and inflammatory parameters. FINDINGS: LDN and inflammatory markers were significantly increased in MOP compared to NWC. Transcriptome analysis showed increased neutrophil-related gene expression signatures associated with inflammation, neutrophil activation, and immunosuppressive function. However, LDN did not suppress T cells proliferation and produced low levels of reactive oxygen species (ROS). Circulating LDN in MOP significantly decreased after bariatric surgery in parallel with BMI, metabolic syndrome, and inflammatory markers. INTERPRETATION: Obesity increases LDN displaying an inflammatory gene signature. Our results suggest that LDN may represent a neutrophil subset associated with chronic inflammation, a feature of obesity that has been previously associated with the appearance and progression of co-morbidities. Furthermore, bariatric surgery, as an efficient therapy for severe obesity, reduces LDN in circulation and improves several components of the metabolic syndrome supporting its recognized anti-inflammatory and beneficial metabolic effects. FUNDING: This work was supported in part by grants from the National Institutes of Health (NIH; 5P30GM114732-02, P20CA233374 - A. Ochoa and L. Miele), Pennington Biomedical NORC (P30DK072476 - E. Ravussin & LSU-NO Stanley S. Scott Cancer Center and Louisiana Clinical and Translational Science Center (LACaTS; U54-GM104940 - J. Kirwan).

Transcriptome and Functions of Granulocytic Myeloid-Derived Suppressor Cells Determine their Association with Disease Severity of COVID-19

COVID-19 ranges from asymptomatic in 35% of cases to severe in 20% of patients. Differences in the type and degree of inflammation appear to determine the severity of the disease. Recent reports show an increase in circulating monocytic-myeloid-derived suppressor cells (M-MDSC) in severe COVID 19, that deplete arginine but are not associated with respiratory complications. Our data shows that differences in the type, function and transcriptome of Granulocytic-MDSC (G-MDSC) may in part explain the severity COVID-19, in particular the association with pulmonary complications. Large infiltrates by Arginase 1+ G-MDSC (Arg+G-MDSC), expressing NOX-1 and NOX-2 (important for production of reactive oxygen species) were found in the lungs of patients who died from COVID-19 complications. Increased circulating Arg+G-MDSC depleted arginine, which impaired T cell receptor and endothelial cell function. Transcriptomic signatures of G-MDSC from patients with different stages of COVID-19, revealed that asymptomatic patients had increased expression of pathways and genes associated with type I interferon (IFN), while patients with severe COVID-19 had increased expression of genes associated with arginase production, and granulocyte degranulation and function. These results suggest that asymptomatic patients develop a protective type I IFN response, while patients with severe COVID-19 have an increased inflammatory response that depletes arginine, impairs T cell and endothelial cell function, and causes extensive pulmonary damage. Therefore, inhibition of arginase-1 and/or replenishment of arginine may be important in preventing/treating severe COVID-19.