Targeting neutrophil cell death as a treatment for multimorbidity

Multimorbidity is the presence of two or more chronic conditions in a single person. Chronic inflammatory disorders account for ~70% of all worldwide deaths, with cardiovascular diseases (e.g., atherosclerosis) and respiratory conditions (e.g., chronic obstructive pulmonary disease (COPD)) frequently presenting together as a multimorbidity, due to shared risk factors. Neutrophilic inflammation is central to the progression of COPD and atherosclerosis, with the dysregulation of neutrophil cell death mechanisms causing prolonged inflammatory responses, damaging the surrounding tissues. This suggests that therapies targeting neutrophil cell death mechanisms (i.e., apoptosis and neutrophil extracellular trap (NET)osis) may be used to treat such conditions. Previous work indicates that the EGFR/ErbB inhibitor, neratinib, induces neutrophil apoptosis and increases efferocytosis rates in macrophages in vivo. Moreover, the PKCβII inhibitor ruboxistaurin has previously been shown to inhibit NET formation. This study presents findings in support of the ideas that: 1) Ruboxistaurin is able to significantly inhibit the production of NETs induced by multiple different pathways in human neutrophils in vitro. 2) Neratinib, is able to induce neutrophil apoptosis, and is also able to increase efferocytosis and phagocytosis rates of human monocyte derived macrophages (MDMs) in vitro (potentially via inducing elevated expression of MerTK on these cells). 3) Using an AAV-mPCSK9 induced model of atherosclerosis (in tandem with a high fat diet (HFD)), and an LPS induced acute lung injury model in combination, it is possible to develop a murine model of multimorbidity in vivo. 4) Using this murine model of multimorbidity, neratinib treatment induced multiple positive outcomes relating to the severity of inflammation observed between groups treated with neratinib and vehicle control groups. These findings suggest that treatments which target neutrophil cell death mechanisms represent viable therapeutic options for use in the treatment of chronic inflammatory disorders, and multimorbidity.