Low P-Selectin Glycoprotein Ligand-1 Expression in Neutrophils Associates with Disease Activity and Deregulated NET Formation in Systemic Lupus Erythematosus

Abstract

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the generation of anti-DNA autoantibodies due to exposure of immune cells to excessive amounts of extracellular DNA. Lack of P-selectin in mice induces the development of a lupus-like syndrome and patients with cutaneous lupus have reduced P-selectin expression in skin vessels. Using flow cytometry we analyzed in healthy donors and patients the expression of P-selectin Glycoprotein Ligand-1 (PSGL-1) in circulating neutrophils and the implication of PSGL-1/P-selectin interaction in neutrophil extracellular traps (NETs) generation. We found a statistical significance that neutrophils from active SLE patients have a reduced expression of PSGL-1 and low levels of PSGL-1 in neutrophils from SLE patients associated with the presence of anti-dsDNA antibodies, clinical lung involvement, Raynaud’s phenomenon, and positive lupus anticoagulant. PSGL-1 is present along the DNA in the NET. In healthy donors, neutrophil interaction with immobilized P-selectin triggers Syk activation, increases the NETs percentage and reduces the amount of DNA extruded in the NETs. In active SLE patients, neutrophil interaction with P-selectin does not activate Syk or reduce the amount of DNA extruded in the NETs, that might contribute to increase the extracellular level of DNA and hence, to disease pathogenesis.

Spleen tyrosine kinase inhibition mitigates hemin-induced thromboinflammation in the lung and kidney of sickle cell mice

“…Third, engagement of PSGL-1 by P-selectin and Eselectin transactivates Syk in leukocytes and reduces neutrophil rolling velocities on Eselectin/ICAM-1 30,[56][57][58][59] . Moreover, neutrophil interaction with immobilized P-selectin triggers Syk activation 60 . Fourth, Syk phosphorylation was also found to be elevated in deoxygenated sickle RBCs and Syk inhibition, was shown to block Band 3 tyrosine phosphorylation preventing the release of extracellular vesicles, inhibiting RBC adhesion to heme-activated endothelial cells and increasing SCD RBC deformability in ex-vivo flow models 34 .…”

PSGL-1, ADAM8, and selectins as potential biomarkers in the diagnostic process of systemic lupus erythematosus and systemic sclerosis: an observational study

“…Moreover, mice lacking PSGL-1 develop an autoimmune syndrome with characteristics similar to SSc ( 29 ). In SLE, PSGL-1 is reduced during disease activity in neutrophils, and lower levels of PSGL-1 in SLE neutrophils are associated with the presence of anti-dsDNA antibodies, clinical lung involvement, Raynaud’s phenomenon, and positive lupus anticoagulant ( 31 ). Additionally, P-selectin is reduced in skin vessels of lupus cutaneous patients, and P-selectin-deficient mice develop a progressive autoimmune syndrome similar to lupus ( 30 ).…”

“…Leukocyte activation induces L-selectin shedding ( 49 ) and could account for the membrane expression reduction; however, we did not find increased sL-selectin levels, suggesting that either L-selectin remains in the cytoplasm or its production is reduced in leukocytes of these patients. Regarding ADAM8 expression, it has primarily focused on cancer, rheumatic diseases, and respiratory diseases, with neutrophils and eosinophils being the main immune cell populations studied ( 23 , 31 , 50 , 51 ). However, regarding the expression of ADAM8 in monocytes, T and B lymphocytes, and dendritic cells, there is scarce information and controversy regarding T cells ( 52 , 53 ).…”

“…In SLE patients, we found that higher sADAM8 levels were associated with the presence of cutaneous involvement and with the presence of anti-dsDNA, clinical manifestations that have been related in previous reports with disease worsening defined by kidney, skin, and brain damage ( 55 , 56 ), and with SLE disease activity ( 55 ). Interestingly, lower levels of PSGL-1 in neutrophils were associated with lung involvement, Raynaud’s phenomenon, and antibodies against dsDNA ( 31 ). With respect to the associations with specific treatments, AZA normalized sPSGL-1 levels to those of HD values.…”

“…Notably, the absence of PSGL-1 in mice leads to an autoimmune syndrome similar to human scleroderma ( 29 ), while the absence of P-selectin results in an autoimmune syndrome resembling human lupus ( 30 ). In SLE patients, neutrophil PSGL-1 expression decreases during active disease phases ( 31 ) while plasma-soluble P-selectin levels increase, correlating with disease activity ( 32 ). In SSc patients, monocytes exhibit a nonfunctional PSGL-1 receptor that fails to trigger syk activation and to produce IL10 upon P-selectin binding ( 33 ).…”