Atherosclerosis stand out as the leading cause of mortality worldwide. The rupture of vulnerable atherosclerotic lesions is the main cause of atherothrombotic events, however the mechanisms underlying the transition from stable to unstable lesions remains poorly understood. Neutrophils are key protagonists during host defense but also mediate tissue injury as collateral damage of their function. Given that, vascular integrity is compromised during atherosclerosis and cell death dictates the outcome of the disease, understanding the mechanisms that orchestrate these processes is of paramount importance. DZHK scientists and their colleagues demonstrate that neutrophils drive a new form of histone-mediated cell death that perpetuates inflammation and favour plaque destabilization. Neutrophil extracellular traps (NETs) act as a source of histone H4 which induce the lysis of smooth muscle cells (SMCs) through the formation of membrane pores, a process that can be targeted therapeutically.
The authors combine different mouse models that pharmacologically or genetically alter circulating numbers of neutrophils in a mouse model atherosclerotic plaque destabilization. Sustained neutropenia or neutrophilia respectively enhances or decreases the signs of instability with a prominent detrimental effect on intimal SMCs but not on macrophages, main cell types composing the atherosclerotic lesion. This novel neutrophil-SMC interplay is sustained by activated SMCs that induce recruitment of infiltrated neutrophils towards them, followed by activation through the release of the chemokine CCL7. SMC-derived CCL7 triggers the release of NETs by neutrophils to the proximities of SMCs which induce their death. NETs are normally released upon neutrophil exposure to microbes to prevent their dissemination. However, during chronic inflammation sterile insults can also trigger NET release, which accumulation lead to tissue injury. Here, taking advance of super resolution microscopy, biophysical techniques and in vitro and in vivo antibody-based blocking approaches, the authors demonstrate that histone H4 contained in the NETs forms pores in the membrane from SMCs which causes cell lysis and promotes the destabilization of the plaque. Using computer modelling techniques, the authors design and synthetize a blocking peptide that specifically interfere with the interaction of histone H4 and the SMC membrane thereby preventing intimal SMC death and ameliorating plaque stability. Histone H4 blocking therapies arise as promising strategies to prevent plaque rupture but also to reduce exacerbated inflammation associated to other cell death-centered diseases such as arthritis, inflammatory bowel disease, sepsis or dementia.
May 2019