Cigarette Smoke Modulates Inflammation and Immunity via Reactive Oxygen Species-Regulated Trained Immunity and Trained Tolerance Mechanisms

Significance: Cigarette smoke (CS) is a prominent cause of morbidity and death and poses a serious challenge to the current health care system worldwide. Its multifaceted roles have led to cardiovascular, respiratory, immunological, and neoplastic diseases. Recent Advances: CS influences both innate and adaptive immunity and regulates immune responses by exacerbating pathogenic immunological responses and/or suppressing defense immunity. There is substantial evidence pointing toward a critical role of CS in vascular immunopathology, but a comprehensive and up-to-date review is lacking. Critical Issues: This review aims to synthesize novel conceptual advances on the immunomodulatory action of CS with a focus on the cardiovascular system from the following perspectives: (i) the signaling of danger-associated molecular pattern (DAMP) receptors contributes to CS modulation of inflammation and immunity; (ii) CS reprograms immunometabolism and trained immunity-related metabolic pathways in innate immune cells and T cells, which can be sensed by the cytoplasmic (cytosolic and non-nuclear organelles) reactive oxygen species (ROS) system in vascular cells; (iii) how nuclear ROS drive CS-promoted DNA damage and cell death pathways, thereby amplifying inflammation and immune responses; and (iv) CS induces endothelial cell (EC) dysfunction and vascular inflammation to promote cardiovascular diseases (CVDs). Future Directions: Despite significant progress in understanding the cellular and molecular mechanisms linking CS to immunity, further investigations are warranted to elucidate novel mechanisms responsible for CS-mediated immunopathology of CVDs; in particular, the research in redox regulation of immune functions of ECs and their fate affected by CS is still in its infancy.