Dysfunctional Rhbdf2 of proopiomelanocortin mitigates ambient particulate matter exposure-induced neurological injury and neuron loss by antagonizing oxidative stress and inflammatory reaction

Highlights

• POMC-specific Rhbdf2 loss (Rhbdf2^Pomc) relieves PM_2.5-induced pathological phenotypes of metabolic dysfunction.

• Rhbdf2^Pomc ameliorates prolonged PM_2.5-triggered peripheral inflammation, hypothalamic oxidative stress injury.

• Rhbdf2 positively contributes to PM_2.5-triggered increases of inflammation and oxidative stress in vitro.

Abstract

Ambient particulate matter (PM_2.5)-induced metabolic syndromes is a critical contributor to the pathological processes of neurological diseases, but the underlying molecular mechanisms remain poorly understood. The rhomboid 5 homolog 2 (Rhbdf2), an essential regulator in the production of TNF-α, has recently been confirmed to exhibit a key role in regulating inflammation-associated diseases. Thus, we examined whether Rhbdf2 contributes to hypothalamic inflammation via NF-κB associated inflammation activation in long-term PM_2.5-exposed mice. Specifically, proopiomelanocortin-specific Rhbdf2 deficiency (Rhbdf2^Pomc) and corresponding littermates control mice were used for the current study. After 24 weeks of PM_2.5 inhalation, systemic-metabolism disorder was confirmed in WT mice in terms of impaired glucose tolerance, increased insulin resistance, and high blood pressure. Markedly, PM_2.5-treated Rhbdf2^Pomc mice displayed a significantly opposite trend in these parameters compared with those of the controls group. We next confirmed hypothalamic injury accompanied by abnormal POMC neurons loss, as indicated by increased inflammatory cytokines, chemokines, and oxidative-stress levels and decreased antioxidant activity. These results were further supported by blood routine examination. In summary, our findings suggest that Rhbdf2 plays an important role in exacerbating PM_2.5-stimulated POMC neurons loss associated hypothalamic injury, thus providing a possible target for blocking pathological development of air pollution-associated diseases.

Introduction

Air pollution presents a considerable challenge to human health. According to the report of World Health Organization (WHO), air contamination is one of the top-eight environmental risks. More than 90 % of the affected population resides in developing countries, and nearly 800,000 citizens have died in the past decade (Atkinson et al., 2014; Cao et al., 2018, Nazrul et al., 2020; Kinney et al., 2011). In particular, the impact of environmental pollution in China has become increasingly serious. Epidemiological surveys have shown that the number of total deaths caused by air pollution in China may be as high as 111,000 (Yuan et al., 2020; Feng and Liao, 2016). Due to the deterioration of air quality, the incidence of lung cancer in China has been increasing at an alarming rate of 26.95 % per year. Particulate matter (PM)—which is also known as haze and consists of particles with sizes less than or equal to 2.5 microns (PM_2.5)—is considered to comprise the majority of air pollutants (Wu et al., 2017; Li et al., 2020). Previous studies have shown that long-term exposure to ambient particulate matter (PM_2.5), directly through the lungs enters the blood and destroys the blood-brain barrier (BBB), which represents a major health threat (Liu et al., 2018; Fu et al., 2018; Xu et al., 2016). In addition, extensive epidemiological surveys have shown that PM_2.5 is a major contributor to type II diabetes mellitus, coronary disease, cerebrovascular disease, pulmonary disease, metabolic disorder, and central nervous system (CNS) diseases (Meo et al., 2015, Dabass et al., 2018; Turner et al., 2017; Xing et al., 2016; Zhang et al., 2019; Xu et al., 2019; Sram et al., 2017). Preliminary studies have found that sustained PM_2.5 inhalation increases metabolic stress and promotes low-grade chronic meta-inflammation and hypothalamic inflammation, the latter of which is accompanied by enhanced astrocytic activation and decreased proopiomelanocortin (POMC) neuronal expression (Xu et al., 2016; Feng et al., 2016; Ge et al., 2017). Unfortunately, the pathogenesis of hypothalamic injury caused by PM_2.5 remains unknown.

Recently, rhomboid 5 homolog 2 (Rhbdf2), an inactive member of the rhomboid intramembrane-proteinase family of serine proteases, plays a key role in regulating protein degradation, intracellular trafficking, and inflammatory responses (Xu et al., 2018; Chen-Xu et al., 2019; Kim et al., 2018). Previous studies have confirmed that in metabolic-syndrome-associated initiation of innate immunity, enhanced Rhbdf2 expression promotes meta-inflammatory responses by increasing TNF-α production via trafficking of the TNF-α-converting enzyme (TACE) (Qing et al., 2018; Chenxu et al., 2018; Luo et al., 2016). These signal transductions can stimulate up-regulation of downstream cascades that involve tumor necrosis factor receptor 1/2 (TNFR1/2), NF-κB, and chemokines or cytokines to promote inflammatory responses, as well as to increase oxidative-stress activity. Importantly, our preliminary work determined that over-expressed Rhbdf2 promoted acute liver injury and the occurrence of systemic-metabolic syndrome (Xu et al., 2019; Ge et al., 2017). However, the correlation and roles of Rhbdf2 in PM-induced hypothalamic injury have not previously been elucidated. Hence, our present study aimed to investigate the potential molecular mechanisms by which Rhbdf2 performs its potential functional regulation in prolonged PM_2.5-triggered hypothalamic injury and pathogenic processes.