Mutant neutrophils and NETosis in clonal hematopoiesis: an emerging contributor of thromboinflammation and organ dysfunction.

UNLABELLED: Age-related proliferation of indeterminate capacity hematopoietic stem and progenitor cells bearing somatic mutations, mainly in DNMT3A, TET2, and ASXL1, is referred to as clonal hematopoiesis of indeterminate potential (CHIP). In addition to the well-known premalignant effects, CHIP causes systemic effects and predisposes to cardiovascular disease, thromboembolism, and dysfunction of multiple organs. Mutant neutrophils have been increasingly recognized as contributors to this pathology. These cells exhibit aberrant phenotypes and epigenetic alterations associated with pro-inflammatory and pro-thrombotic phenotypes that may favor NET formation. Uncontrolled NETosis may promote endothelial damage, platelet aggregation, and microvascular thrombosis that creates a vicious loop of thromboinflammation. The association of CHIP-related NETosis with venous and arterial thromboses, ischemic stroke, myocardial infarction, and organ-specific damage has been reported, although the main contribution is largely referred from indirect biomarker-based evidence or extrapolation from related conditions. Instead of detecting NET production directly, several studies employ indirect NET markers (such as MPO-DNA, citH3, and cfDNA). Activation of PAD4, generation of reactive oxygen species and inflammatory cytokines are the main modulators implicated in mechanistic studies. Clinically, therapies against NETs using DNase, PAD4, or cytokine blockade have the potential to reduce the risk of thromboinflammation. Although supported by compelling preclinical and observational evidence, there are still challenges because of the use of retrospective studies, murine models, and indirect measure of NET.The current evidence base consists primary of preclinical (murine and in vitro) studies along with observational human data. Future studies are required on prospective trials, mutation-directed biomarkers, and precision medicine modalities to regulate mutant neutrophil functions. Insight into NET-mediated pathogenesis in CHIP does not just clarify the pathways between clonal hematopoiesis and thromboinflammation and dysfunction in the body but also provides opportunities to formulate specific solutions to decrease cardiovascular and systemic illnesses in victims.

GRAPHICAL ABSTRACT: [Image: see text]