Targeted inhibition of necroptosis could be a promising new approach to treating chronic obstructive pulmonary disease (COPD).
Necroptosis refers to a regulated form of necrosis that does, however, have damaging effects. Although it shares with apoptosis the activation of death receptors (such as the Fas receptor) the cells subsequently initiate a kind of self-digestion. In necroptosis, the cell bursts and releases its contents into the surrounding tissues, leading to an immune response. This constitutes a driving force for inflammation and destruction of the tissue.
Apoptosis also plays an important role in COPD, but it represents a more organised form of cell death that, unlike necroptosis, is usually not proinflammatory because no cell contents are released. Australian and Belgian researchers report in a recent study in the American Journal of Respiratory and Critical Care Medicine that necroptosis can be triggered by cigarette smoke and occurs with increased frequency in the lungs of COPD patients, and also in specialised mouse models of COPD.1,2
The scientists investigated and compared the occurrence of cell death, necroptosis-related mRNA and proteins in the lungs and lung macrophages of mice with cigarette smoke-induced experimental COPD, wild-type mice, as well as COPD patients and healthy controls.
Among the proteins, RIPK3 and MLKL are considered central, as the signalling pathway of necroptosis depends on them. MLKL (Mixed lineage kinase domain-like protein) is a pseudokinase that plays a key role in TNF-induced necroptosis. RIPK3 (Receptor-interacting serine/threonine-protein kinase) is also a component of the TNF receptor signalling pathway and can trigger necroptosis by interacting with RIPK1 and MLKL (this protein complex is called the necrosome).3 Phosphorylated MLKL is thought to create pores in the plasma membrane, leading to uncontrolled cell swelling (ischemic cell death, also known as oncosis) and rapid rupture of the plasma membrane.4
Compared to non-smokers and smokers without COPD, lung tissues from COPD sufferers had higher levels of the MLKL and phospho-MLKL proteins, but not RIPK3.
Levels of necroptosis-type mRNA and these proteins were also elevated in mice with experimental (cigarette smoke-induced) COPD. However, knockout mice with a deletion of the RIPK3 or MLKL gene showed no airway inflammation in response to cigarette smoke.
More specifically, the absence of RIPK3 reduced airway inflammation and remodelling as well as the development of emphysematous pathologies following chronic smoke exposure. A combined inhibition of apoptosis (pan-caspase inhibitor) and necroptosis (MLKL deletion) was also investigated. The latter also resulted in a reduced inflammatory response to smoke, but only knockout of MLKL prevented lung injury and emphysema development. All three interventions together (RIPK3 deletion, MLKL deletion and pan-caspase inhibitor) were able to reduce cigarette smoke-induced lung cell death.
Thus, inhibition of necroptosis reduced smoking-induced airway inflammation, which was associated with less lung tissue remodelling and emphysema development.
COPD is responsible for significant disability worldwide and is a leading cause of death. Currently, there are no treatments that can halt or reverse its progression. Therefore, targeting inhibition of this pathway appears to be an exciting candidate for further research.
References:
1. Inhibition of necroptosis may be a new therapeutic approach to treating COPD. News-Medical.net https://www.azolifesciences.com/news/20210621/Inhibition-of-necroptosis-may-be-a-new-therapeutic-approach-to-treating-COPD.aspx (2021).
2. Lu, Z. et al. Necroptosis Signalling Promotes Inflammation, Airway Remodelling and Emphysema in COPD. Am J Respir Crit Care Med (2021) doi:10.1164/rccm.202009-3442OC.
3. RIPK3 receptor interacting serine/threonine kinase 3 [Homo sapiens (human)] - Genes - NCBI. https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=11035. Linkermann, A., Kunzendorf, U. & Krautwald, S. Phosphorylated MLKL causes plasma membrane rupture. Mol Cell Oncol 1, e29915 (2014).