Nitric oxide and peroxynitrite trigger and enhance release of neutrophil extracellular traps.

Despite great interest, the mechanism of neutrophil extracellular traps (NETs) release is not fully understood and some aspects of this process, e.g. the role of reactive nitrogen species (RNS), still remain unclear. Therefore, our aim was to investigate the mechanisms underlying RNS-induced formation of NETs and contribution of RNS to NETs release triggered by various physiological and synthetic stimuli. The involvement of RNS in NETs formation was studied in primary human neutrophils and differentiated human promyelocytic leukemia cells (HL-60 cells). RNS (peroxynitrite and nitric oxide) efficiently induced NETs release and potentiated NETs-inducing properties of platelet activating factor and lipopolysaccharide. RNS-induced NETs formation was independent of autophagy and histone citrullination, but dependent on the activity of phosphoinositide 3-kinases (PI3K) and myeloperoxidase, as well as selective degradation of histones H2A and H2B by neutrophil elastase. Additionally, NADPH oxidase activity was required to release NETs upon stimulation with NO, as shown in NADPH-deficient neutrophils isolated from patients with chronic granulomatous disease. The role of RNS was further supported by increased RNS synthesis upon stimulation of NETs release with phorbol 12-myristate 13-acetate and calcium ionophore A23187. Scavenging or inhibition of RNS formation diminished NETs release triggered by these stimuli while scavenging of peroxynitrite inhibited NO-induced NETs formation. Our data suggest that RNS may act as mediators and inducers of NETs release. These processes are PI3K-dependent and ROS-dependent. Since inflammatory reactions are often accompanied by nitrosative stress and NETs formation, our studies shed a new light on possible mechanisms engaged in various immune-mediated conditions.

Immunomodulatory Role of Vitamin D: A Review.

Vitamin D is well known for its classical hormonal action related to the maintenance of mineral and skeletal homeostasis. However, the discovery that vitamin D receptor (VDR) is expressed in most non-skeletal tissues points to its broad role in the human organism. Current literature emphasizes a multidirectional role of vitamin D, with a special focus on its immunomodulatory properties. As VDR and the enzyme 1-α-hydroxylase are expressed in most immune cells, vitamin D modulates the phagocytic activity of macrophages and natural killer cells. In addition, it induces the microbicidal activity of phagocytes. In contrast, vitamin D suppresses differentiation and maturation of antigen-presenting dendritic cells and B lymphocytes, and it inhibits proliferation of Th1 and Th17 cells. In this review we aimed to describe the current scientific discoveries on the role of vitamin D as immunomodulator.