Epidemiological investigation shows that, the level of PM2.5 in the air is positively related to the incidence and prevalence of respiratory inflammatory diseases (such as asthma), and can also lead to cardiovascular and other systemic diseases 22,23. At present, the mechanism of haze (PM2.5) mainly includes local and systemic inflammatory response and oxidative stress. According to the existing investigation results, haze hazards are mainly manifested as acute effects, and its health effects are mainly manifested as acute respiratory inflammation, cardiovascular system disorder, and significant increase in the incidence and mortality of cardiopulmonary diseases 24. The earliest health effect of the body after short-term exposure to pollutants (24 hours) is the activation of pulmonary inflammation and oxidative stress pathway 25.
In addition to acting as a physical barrier against inhalation of toxic substances, respiratory epithelial cells can also participate in the occurrence and development of respiratory diseases through the release of inflammatory mediators. During the stimulation of harmful factors, airway epithelium and innate immune cells can release DAMP (damage related molecular model) molecules, and then activate the innate and acquired immunity of airway, releasing more inflammatory mediators. They interact with airway epithelium, and form a complex cytokine regulatory network, and trigger and promote the occurrence of asthma 26.
It was found that TLR2 and TLR4 can bind to HMGB1 secreted by macrophages and neutrophils, which promotes NF-κB activation and induces inflammation. This indicated that TLR2 and TLR4 are the receptors of HMGB1. Recent studies have shown that HMGB1-DNA complex is not a single molecule, but a HMGB1-DNA complex 27. Tian et al. confirmed that HMGB1-DNA complex can enter cells and activate intracellular receptors with the assistance of RAGE, thus activating TLR9 signaling pathway, promoting immune cell maturation and cell molecular secretion through TLR9 28. However, some experiments have confirmed that HMGB1-DNA can inhibit immune response or cause autophagy in some types of cells 29. In addition, the activation pathway of rage mediated by HMGB1 is different from that of TLR4 mediated by HMGB1. The former only activated IKKβ, while the latter activated IKKα and IKKβ. Therefore, it can be seen that the signal transduction process of HMGB1 acting on cells is very complex, and it may activate cells to participate in related pathophysiological reactions in many ways.
Recently, when exploring the role of HMGB1-TLRs signaling pathway in ischemia-reperfusion injury, researchers found that human interference with the interaction of HMGB1-TLRs and blocking the activation of downstream signaling pathway can weaken the cascade reaction of inflammation and immune response triggered in the process of injury 30–32. The previous work of our group found that TLR4 was involved in inducing the synthesis of TNFα in human macrophages by silica, and mediated the development of inflammation.
Hepatocytes can directly clear LPS from the bloodstream through hepatic uptake via TLR4, indicating their important role in inflammatory responses 33. Both epidemiologic and controlled exposure studies in humans and animals have demonstrated an association between air pollution exposure and metabolic disorders such as diabetes 34. It was also found that IL-6 levels were elevated in blood, liver, adipose tissue, and macrophages, which induced activation of the STAT3/SOCS3 pathway in liver 35. Prenatal exposure to diesel exhaust PM (DEP) programmed the development of Non-alcoholic fatty liver disease (NAFLD) differently in the adult male offspring of mice fed normal chow and a high-fat diet, showing the pleotropic effects of exposure to adverse environmental factors in early life 36.
Future studies are anticipated to make broad conceptual contributions, beyond the innate immunity field, to the understanding of essentials of cell biology.