RIPK1 kinase-dependent inflammation and cell death contribute to the pathogenesis of COPD

Abstract

RationaleReceptor-interacting protein kinase 1 (RIPK1) is a key mediator of regulated cell death (including apoptosis and necroptosis) and inflammation, both drivers of chronic obstructive pulmonary disease (COPD) pathogenesis.ObjectiveWe aimed to define the contribution of RIPK1 kinase-dependent cell death and inflammation in the pathogenesis of COPD.MethodsWe assessedRIPK1expression in single-cell RNA-sequencing data from human and mouse lungs and validated RIPK1 levels in lung tissue of COPD patientsviaimmunohistochemistry. Next, we assessed the consequences of genetic and pharmacological inhibition of RIPK1 kinase activity in experimental COPD, usingRipk1S25D/S25Dkinase deficient mice and the RIPK1 kinase inhibitor GSK'547.Measurements and main resultsRIPK1expression increased in alveolar type I (AT1), AT2, ciliated and neuroendocrine cells in human COPD. RIPK1 protein levels were significantly increased in airway epithelium of COPD patients, compared to never smokers and smokers without airflow limitation. In mice, exposure to cigarette smoke (CS) increasedRipk1expression similarly in AT2 cells, and further in alveolar macrophages and T cells. Genetic and/or pharmacological inhibition of RIPK1 kinase activity significantly attenuated airway inflammation upon acute and subacute CS-exposure, as well as airway remodeling, emphysema and apoptotic and necroptotic cell death upon chronic CS-exposure. Similarly, pharmacological RIPK1 kinase inhibition significantly attenuated elastase-induced emphysema and lung function decline. Finally, RNA-sequencing on lung tissue of CS-exposed mice revealed downregulation of cell death and inflammatory pathways upon pharmacological RIPK1 kinase inhibition.ConclusionsRIPK1 kinase inhibition is protective in experimental models of COPD and may represent a novel promising therapeutic approach.

Mitochondria-Targeted Antioxidants as a Therapeutic Strategy for Chronic Obstructive Pulmonary Disease

“…In addition, oxidative stress in the lungs regulates nuclear histone modification such as methylation, acetylation, and phosphorylation that is suggested to cause chromatin remodeling, recruitment of basal transcription factors, and RNA polymerase II, leading to increased pro-inflammatory responses [ 40 , 41 , 42 ]. Studies have reported that CS-induced mtROS in COPD patients contributes to an alteration in mitochondrial fission and fusion proteins [ 44 , 45 , 46 ], increased oxidative stress gene signatures [ 47 ], lower mitochondrial membrane potential and ATP levels [ 48 ], impaired mitophagy and concomitant aggregation of damaged and dysfunctional mitochondria [ 35 , 49 , 50 ], and necrosis [ 51 , 52 , 53 ]. In line with this, immune cells in COPD exhibit altered metabolic function, including glycolysis and fatty acid oxidation [ 54 , 55 , 56 , 57 , 58 ], which are important processes required for ATP production to fuel energy demanding immune functions [ 59 ].…”

Cell type‐specific molecular mechanisms and implications of necroptosis in inflammatory respiratory diseases

“…Cigarette smoking exposure remains a dominating risk factor for developing COPD, which contributes to the imbalance in inflammatory response, and necroptosis of epithelial cells in the lungs 43 . Among the core necroptotic regulators, RIPK1 protein is notably overexpressed in the airway epithelium of COPD patients versus never‐smokers and smokers without airflow limitation 44 . Meanwhile, phosphorylated MLKL is notably induced in the advanced stages of cigarette smoke‐mediated emphysema in pulmonary epithelial cells while apoptotic signals can be maximally induced in the early stages of cigarette smoking exposure 45 .…”

“…43 Among the core necroptotic regulators, RIPK1 protein is notably overexpressed in the airway epithelium of COPD patients versus neversmokers and smokers without airflow limitation. 44 MUC1 (mucin 1) is a membrane-tethered mucin glycoprotein, which is primarily expressed on the surface of airway epithelial cells. 46 In addition to anti-inflammation and anti-apoptosis against infection, 47,48 MUC1 expression is elevated in airway epithelial cells in response to TNF-α, and interacts with RIPK1 but not with RIPK3.…”

Revealing a potential necroptosis‐related axis (RP11‐138A9.1/hsa‐miR‐98‐5p/ZBP1) in periodontitis by construction of the ceRNA network

“…7 Inflammation and cell death are two distinct but highly interconnected and mutually regulated phenomena that are important in immune defense, pathogenesis, and maintaining organismal homeostasis. 8,9 Both inflammation and cell death are also recognized as host-mediated mechanisms that facilitate the elimination of invading pathogens. 10 Despite progress in understanding periodontitis, many challenges remain in uncovering the molecular mechanisms behind its pathogenic processes, necessitating further research.…”

“…Microbial infection and host immune‐inflammatory responses are the key factors affecting the pathogenesis of periodontitis 7 . Inflammation and cell death are two distinct but highly interconnected and mutually regulated phenomena that are important in immune defense, pathogenesis, and maintaining organismal homeostasis 8,9 . Both inflammation and cell death are also recognized as host‐mediated mechanisms that facilitate the elimination of invading pathogens 10 .…”