Smoker's macrophages

Smoker's macrophages are alveolar macrophages whose characteristics, including appearance, cellularity, phenotypes, immune response, and other functions, have been affected upon the exposure to cigarettes. These altered immune cells are derived from several signaling pathways and are able to induce numerous respiratory diseases. They are involved in asthma, chronic obstructive pulmonary diseases (COPD), pulmonary fibrosis, and lung cancer. Smoker’s macrophages are observed in both firsthand and secondhand smokers, so anyone exposed to cigarette contents, or cigarette smoke extract (CSE), would be susceptible to these macrophages, thus in turns leading to future complications.

Alveolar macrophages are crucial in processing inhaled substances including cigarette chemicals and particulate matter. The chemicals in tobacco, such as nicotine, tar, and carbon monoxide, stimulate several physiological pathways, which influence the recruitment and functions of these macrophages. Some of the smoker’s macrophages are recruited from the circulating monocytes while some are the original alveolar macrophages residing in the lung. The biochemical processes also lead to immunomodulation and dysregulated repair processes, so the malfunction of macrophages renders individuals more susceptible to infections. In addition, these inhaled substances can enter the bloodstream, especially nicotine which is rapidly transported to the brain, leading to addiction; it will subsequently distributed throughout the body, leading to carcinoma in the future. The morbidity of cigarette smoking is nearly 50% with 7 million first-hand smokers and 1.2 millions second hand smokers killed each year. Regardless of active or passive smokers, macrophage accumulation is found in the lungs. The diagnostic methods for smoke-related diseases include bronchoalveolar lavage which can also be used for examining smoker's macrophages in addition to augmented inflammatory cells in the alveolar lumen.

Appearance

Autofluorescence The uptake of tar from cigarettes accumulates in alveolar macrophages and causes autofluorescence. The intensity of fluorescence, however, is independent of cigarette exposure. This indicates a maximum capacity of tar uptake; excess tar cannot be retained by macrophages. Another pigment in smoker’s macrophage is hemosiderin which is involved in iron homoeostasis. Hemosiderin-laden pigmented macrophages are yellowish brown and found in the bronchiole and peribronchiolar alveolar space. The presence of these dirty macrophages has been a characteristic of many smoke-related lung diseases.

Physiological pathways mediating macrophage changes

Macrophage Polarization A macrophage can be polarized into the classic M1 or M2 phenotype, and this phenomenon can be seen in cigarette consumption. In this polarization scheme, lower M1 markers and higher M2 markers have been observed. The reprogram of macrophage implies a dysregulated inflammation that can damage healthy lung cells. Macrophage polarization is mediated by three major signaling pathways: NF-κB, MAPK, and JAK/STAT. Each signaling cascade can lead to different results depending on the length of smoke history. It is therefore important to evaluate the characteristics of research participants and specify the experimental conditions when examining smoker’s macrophages. It is anticipated that cigarette smoking inhibits signal transduction which alters gene expression and cytokine profile with increasing M2-like phenotype. This trait is involved in anti-inflammation and tissue repair, but this can also be pro-fibrotic. However, some studies found variation in the conventional polarization and found dual polarization in multiple diseases, yet the direction and extent of polarization are also different across diseases. Despite the contradiction, treatments targeting the polarization process have promising results.

NF-κB In long-term smoking or established diseases, not only does CSE decrease the production of pro-inflammatory cytokines, but also impairs TLR2 and TLR4 signaling. Its inhibitory effect on NF-κB also induces apoptosis of alveolar macrophage. Prolonged exposure to CSE hence leads to M2 polarization. Meanwhile, NF-κB pathways will be activated with low concentration of CSE or in previously unexposed individuals. The increased activity of NF-κB upregulates the production of pro-inflammatory cytokines TNF-α, IL-1β, and IL-8. The short-term exposure attracts macrophages and neutrophils to the lung with a 4-fold increase in cellularity. Short duration also biases polarization towards M1 phenotype. The number of immune cells however will be normalized in 6 months, demonstrating the shift in signaling direction.

MAPK Similar time and dose dependent effects of CSE are exerted on macrophage polarization through the MAPK signaling pathway which involves JNK and ERK as intermediate signaling molecules. In diseased conditions due to long-term smoking, the inactivation of JNK reduces the levels of reactive nitrogen species and pro-inflammatory cytokines with more M2-like phenotype. However, brief exposure to CSE triggers the activation of ERK that increases MUC1, TNF-a, and IL-8 levels to produce inflammatory effects.

JAK/STAT Cigarette contents also modulate multiple STAT proteins activities. In response to the smoking, STAT3 and STAT6 signaling are stimulated to potentiate M2-like phenotype with elevated IL-6, IL-10, IL-12, and TGF-b. In the meantime, the toxic nitrogenous chemicals and oxidative stress would be reduced. In post-smoke situations, reduction in STAT1 is associated with M1-like phenotype and the downregulation of IFN-γ signaling.

Cholinergic Anti-inflammatory pathway Nicotine in cigarettes modulates the above signaling pathways by binding to α-7 nicotinic receptors on macrophage or neurons, hence activating the cholinergic anti-inflammatory pathway. Changes can thus be directly mediated by binding of nicotine to macrophage or indirectly via the Vagus nerve. Upon binding, the inhibition of the NF-κB and activation of JAK2/STAT3 pathways lead to over-inhibition of pro-inflammatory cytokines and thus an imbalance toward anti-inflammatory cytokines. The result may be lethal if inflammation is not controlled.

Function abnormalities

Iron homeostasis

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