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

Abstract

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.

Keywords: cell death; cigarette smoke; immunometabolism; morphine; trained immunity; trained tolerance.

FIG. 1.

The concept of trained immunity and trained tolerance. Trained immunity involves metabolic reprogramming and epigenetic modification of the innate immune cells, allowing qualitatively and quantitatively adjusted responses of innate immune cells to subsequent time-delayed heterologous stimulation. Inappropriate trained immunity response can contribute to disease progression, resulting in either a chronic hyperinflammatory state or a persistent state of immunological tolerance.

FIG. 2.

Several DAMP receptor pathways induce innate immune memory (trained immunity) and sustained inflammation, tissue remodeling, and damage. CS promotes disease risk factors by binding to its receptors and induces bioenergetic metabolic reprogramming to induce trained immunity pathology. CS, cigarette smoke; DAMP, danger-associated molecular pattern.

FIG. 3.

The concept of trained immune tolerance. Upon LPS stimulation, itaconate production is increased by CAD/IRG1 transcription. Overproduction of itaconate activates the antioxidant transcription factor Nrf2 by alkylation Keap1, which induces the transcription of various Nrf2-dependent antioxidant and anti-inflammatory genes. Itaconate can also inhibit SDH and reduce ROS generation and IL-1β secretion. Itaconate promotes the transcription of ATF3, which directly inhibits the IκBζ expression to reduce IL-6 secretion. In addition, itaconate directly alkylates the cysteine residue 22 of GAPDH and ALDOA to inhibit glycolysis, and reduces IL-1β secretion, thereby alleviating the inflammatory response. CS exposure can significantly increase the expression of IRG1 and the abundance of itaconate metabolites. ALDOA, aldolase, fructose-bisphosphate A; ATF3, activating transcription factor 3; CAD, cis-aconitate decarboxylase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IκBζ, inhibitor of nuclear factor-kappa B zeta; IL, interleukin; IRG1, immune responsive gene 1; LPS, lipopolysaccharide; Keap1, kelch-like ECH-associated protein 1; Nrf2, nuclear factor erythroid 2-related factor 2; ROS, reactive oxygen species; SDH, succinate dehydrogenase.

FIG. 4.

The schematic figure showed that CS and nicotine induce endothelial dysfunction by binding to different types of DAMP receptors and causing direct damage to endothelial cells, decreasing eNOS and NO bioavailability leading to increased oxidative stress and adhesion molecules, therefore increasing inflammatory response and vascular inflammation to promote initiation and progression of cardiovascular diseases. eNOS, endothelial nitric oxide synthase; NO, nitric oxide.

FIG. 5.

Our working model. Representative model of innate immune memory and immune tolerance response. After initial exposure to the first stimulus, innate immune cells with “memory” traits respond rapidly with a high magnitude of immune response to the secondary stimulation, increased proinflammatory mediators mediated by metabolic reprogramming such as increased aerobic glycolysis, increased acetyl CoA generation, increased mevalonate synthesis, glutaminolysis, and increased production of fumarate and lactate as well as epigenetic modification such as increased H3K27ac and H3K4me3. Also, after exposure to the first stimulus, cells respond with a decreased magnitude of innate immune response (tolerance) characterized by decreased proinflammatory and increased anti-inflammatory mediators mediated by metabolic reprogramming such as decreased aerobic glycolysis, increased production of itaconate metabolites, as well as epigenetic rewiring such as increased and H3K9me3. H3K4me3, histone 3 lysine 4 trimethylations; H3K9me3, histone 3 lysine 9 trimethylation; H3K27ac, histone 3 lysine 27 acetylations.

FIG. 6.

Our working model. The carcinogenic and immunomodulatory toxins in CS bind to different receptors on the cell membrane, cytosol, and nucleus leading to increased cytoplasmic (cytosolic and non-nucleus organelle) ROS, which further induces five different nuclear ROS. Increased ROS production results in the induction of seven types of cell death and subsequent alarmins and neutrophil extracellular trap release, which amplify inflammation and induce trained immunity. Metabolic reprogramming induced by CS can induce epigenetic remodeling and exacerbate immune repose to induce trained immunity. CS exposure significantly upregulates the IRG1 expression and increases the abundance of itaconate metabolites resulting in immunosuppression. The anti-inflammatory effect of CS is counteracted by the proinflammatory effect of other CS constituents resulting in reduced immunosuppression effects and increased inflammation and trained immunity in a phenomenon known as inflammation paradox1 or second inflammation wave. AChR, acetylcholine receptor; CLRs, C-type lectin receptors; GPCRs, G-protein-coupled receptors; NLRs, NOD-like receptors; PAMPs, pathogen-associated molecular patterns; RAGE, receptor for advanced glycation end products; RLRs, retinoic acid-inducible gene-like receptors; TREMs, triggering receptors expressed on myeloid cells; TLRs, toll-like receptors.