The role of neutrophils and NETosis in autoimmune and renal diseases

Abstract

Systemic autoimmune diseases are a group of disorders characterized by a failure in self-tolerance to a wide variety of autoantigens. In genetically predisposed individuals, these diseases occur as a multistep process in which environmental factors have key roles in the development of abnormal innate and adaptive immune responses. Experimental evidence collected in the past decade suggests that neutrophils — the most abundant type of white blood cell — might have an important role in the pathogenesis of these diseases by contributing to the initiation and perpetuation of immune dysregulation through the formation of neutrophil extracellular traps (NETs), synthesis of proinflammatory cytokines and direct tissue damage. Many of the molecules externalized through NET formation are considered to be key autoantigens and might be involved in the generation of autoimmune responses in predisposed individuals. In several systemic autoimmune diseases, the imbalance between NET formation and degradation might increase the half-life of these lattices, which could enhance the exposure of the immune system to modified autoantigens and increase the capacity for NET-induced organ damage. This Review details the role of neutrophils and NETs in the pathophysiology of systemic autoimmune diseases, including their effect on renal damage, and discusses neutrophil targets as potential novel therapies for these diseases.

Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis

“…Given the critical role that inflammatory cell death processes play in the pathogenesis of SLE, therapeutics that inhibit inflammatory forms of cell death, that enhance clearance or that limit certain deleterious posttranslational modifications may prove to be efficacious in the treatment of SLE. Previous groups have successfully inhibited NETosis and reduced disease activity by using molecules that scavenge ROS, inhibit PAD activation, modulate intracellular and extracellular calcium pools, block MPO activation, and disrupt the stabilization of the actin cytoskeleton (170). Given the critical role of DNASE1L3 in the degradation of DNA in circulating apoptotic microparticles and prevention of autoimmunity in mice (126), examining the effect of DNASE1L3 in SLE patients should be explored.…”

Factor XII and uPAR upregulate neutrophil functions to influence wound healing

“…The fibrin scaffold generated by this synergism entraps microbes within microvessels, limiting the systemic spread of infection while enhancing the clearance of pathogens by activated leukocytes (84,85). In contrast with what occurs in the infectious setting, neutrophils can damage host tissues, contribute to the development of autoimmunity, and lead to a multitude of adverse outcomes (82,(86)(87)(88). In these latter scenarios, the contribution of FXII to neutrophil activation may be maladaptive and, among other outcomes, leads to persistent wound inflammation and impaired wound healing.…”

Neutrophil extracellular traps in acute chorioamnionitis: A mechanism of host defense

“…Sterile inflammation is induced by danger signals termed damage-associated molecular patterns (DAMPs) 89 or alarmins 90 , derived from necrotic cells or cellular stress 91 . NETs can also be formed in sterile inflammation since both alarmins and pathogen-associated molecular patterns (PAMPs) use the same sensor molecules or pattern recognition receptors 92 . Particularly, the high-mobility group box-1 (HMGB1, a prototypical alarmin 93, 94 ) protein can induce NET formation via TLR4 95 , which is the sensor molecule for lipopolysaccharide from Gram negative bacteria 96 .…”

“…The fact that HMGB1 induces NETs is relevant since: (1) amniotic fluid HMGB1 concentrations are higher in women with intra-amniotic infection 97 or clinical chorioamnionitis 98 than in those without these clinical conditions; (2) patients with sterile intra-amniotic inflammation and high amniotic fluid HMGB1 concentrations delivered earlier than those with low concentrations of this alarmin 85 ; (3) the intra-amniotic administration of HMGB1 induces preterm labor and birth in mice 99 ; and (4) the chorioamniotic membranes from women who underwent spontaneous preterm labor releases high concentrations of HMGB1 100 . Alarmin-induced NETs can exacerbate immune responses by directly causing tissue damage 92 . Together, these data suggest that in the setting of sterile intra-amniotic inflammation, chorioamniotic neutrophils form NETs in response to danger signals derived from the amniotic fluid or the chorioamniotic membranes which, in turn, could aggravate the local immune response observed in acute chorioamnionitis.…”