The involvement of copper, circular RNAs, and inflammatory cytokines in chronic respiratory disease

Chronic respiratory diseases (CRDs) are diseases of the airways and other structures of the lung that are the most common non-communicable diseases worldwide. In 2017, approximately 545 million people in the world were estimated to suffer from CRDs, with an increase of 39.8% since 1990 (Collaborators, 2020). Inflammation is the most common CRD pathological manifestation (Aghasafari, 2019; Barnes et al., 2015), commonly accompanied by dysregulated cytokine production (Hong et al., 2017; Ouyang and O'Garra, 2019), and in particular IL-6 and IL-8 (De Moraes et al., 2014; Higham et al., 2018). High levels of plasma IL-6 and IL-8 have been observed in chronic obstructive pulmonary disease (COPD) patients.

Copper is a naturally occurring heavy metal that is essential to life, playing an important role in the maturation and function of lung immune cells, the development of the airway microbiome, and disease (Gehring et al., 2015; Healy et al., 2021; Tanrikulu et al., 2011). At high concentrations, copper can be toxic. Copper exposure has been associated with increased levels of inflammatory cytokines (Ma et al., 2020; Reisgen et al., 2020; Samet et al., 1998) as well as an increased risk for CRDs (Healy et al., 2021; Zhang et al., 2021). However, how these associations are connected is not well understood.

Epigenetic modulation of noncoding RNAs contributes to the development of several CRDs including asthma, COPD, lung cancer, and emphysema (Li et al., 2019; Lou et al., 2020; Shen et al., 2020). Circular RNAs (circRNAs) are noncoding RNAs that play a role in cell proliferation, metastasis, cell cycle progression, and apoptosis (Kristensen et al., 2019). Aberrant expression of circRNAs has been reported to be associated with lung cancer, acute respiratory distress syndrome, tuberculosis (Liu et al., 2020; Wan et al., 2016; Wang et al., 2019), as well as pulmonary inflammation caused by exposure to environmental chemicals such as neodymium-oxide (Hua et al., 2019; Xue et al., 2020), arsenic (Xiao et al., 2018) and cadmium (Chen et al., 2021; Wang et al., 2021). For copper, only one study in plants has found differentially expressed circRNAs following copper treatment (Fu et al., 2019). The effect of copper on the expression of circRNAs in CRDs or pulmonary inflammation has not been reported.

Herein, we evaluated expression of circRNAs in CRD. We identified nine CRD-related circRNAs and evaluated the association of these circRNAs with urinary copper exposure and the inflammatory cytokines, IL-6 and IL-8. The evaluation was completed with 101 CRD patients and 161 healthy control subjects in Shijiazhuang, China. We found decreased circ_0008882 levels to be associated with higher levels of plasma copper and inflammatory cytokines. The role of circ_0008882 in airway inflammation, induced by copper, was assessed in vitro.