Malondialdehyde–Acetaldehyde‐Adducted Surfactant Protein Alters Macrophage Functions Through Scavenger Receptor A

Abstract

Background Reactive aldehydes like acetaldehyde and malondialdehyde generated as a result of alcohol metabolism and cigarette smoke exposure lead to the formation of malondialdehyde-acetaldehyde-adducted proteins (MAA adducts). These aldehydes can adduct to different proteins such as bovine serum album (BSA) and surfactant proteins A or D (SPA, SPD). Macrophages play an important role in innate immunity, but the effect of MAA adducts on macrophage function has not yet been examined. Because macrophage scavenger receptor A (SRA; CD204) mediates the uptake of modified proteins, we hypothesized that the effects of MAA modified proteins on macrophage function are primarily mediated through SRA. Methods and Results We tested this hypothesis by exposing SPD-MAA to macrophages and measuring functions. SPD-MAA treatment significantly stimulated pro-inflammatory cytokine TNF-α release in the macrophage cell line, RAW 264.7. A significant reduction in phagocytosis of zymosan particles was also observed. SPD-MAA stimulated a significant dose-dependent increase in TNF-α and IL-6 release from peritoneal macrophages of WT mice. But a significantly less TNF-α and IL-6 were released from peritoneal macrophages of SRA−/− mice. We observed a significant reduction in phagocytosis of zymosan particles in peritoneal macrophages from WT mice treated with SPD-MAA. No further SPD-MAA-induced reduction was seen in peritoneal macrophages form SRA−/− mice. SPD-MAA treatment significantly increased SRA mRNA expression, but had no effect on surface receptor protein expression. Protein kinase C alpha inhibitor and NF-κB inhibitor significantly reduced pro-inflammatory cytokine release in response to SPD-MAA. Conclusion In conclusion, our data demonstrate that SRA is important for MAA-adducted protein-mediated effect on macrophage functions.

Malondialdehyde–Acetaldehyde (MAA) Protein Adducts Are Found Exclusively in the Lungs of Smokers with Alcohol Use Disorders and Are Associated with Systemic Anti‐MAA Antibodies

“…Consistent with our mouse study (McCaskill et al, 2011) positive MAA-adduct staining was observed only in BAL macrophages from AUD subjects who smoked cigarettes. This result also supports our previous in vitro finding that MAA-adducted protein, once formed, rapidly binds to both macrophages (Sapkota et al, 2016) and airway epithelium (Berger et al, 2014). This rapid uptake of MAA-adducted protein by mouse macrophages requires the expression of scavenger receptor A (Sapkota et al, 2016).…”

“…This result also supports our previous in vitro finding that MAA-adducted protein, once formed, rapidly binds to both macrophages (Sapkota et al, 2016) and airway epithelium (Berger et al, 2014). This rapid uptake of MAA-adducted protein by mouse macrophages requires the expression of scavenger receptor A (Sapkota et al, 2016). Several previous studies report that scavenger receptor A (CD204) is the major receptor that binds MAA-adducted proteins (Duryee et al, 2005; Berger et al, 2014).…”

Structure, genetics and function of the pulmonary associated surfactant proteins A and D: The extra-pulmonary role of these C type lectins

“…Mikerov et al demonstrated that oxidation, by in vivo and in vitro exposure to ozone, can reduce the ability of SP-A to enhance macrophage phagocytosis (Mikerov et al, 2008). Similarly, SP-D exposed to metabolites from alcohol and smoking, known as malondialdehyde-acetaldehyde-adducted proteins (MAA adducts), may result in a pro- inflammatory response via up regulation of TNF-α and IL-6 in pulmonary macrophages (Sapkota et al, 2016). …”

Genetic variants of SP‐D confer susceptibility to radiation pneumonitis in lung cancer patients undergoing thoracic radiation therapy

“…Surfactant protein D (SP‐D), a component of lung surfactants, which reduces surface tension at the pulmonary air–liquid interface and enhances defense against pathogens as the first line of innate pulmonary immunity, has never been investigated with regard to the association between its genetic variants and the risk of RP. Previous study showed that serum levels of SP‐D in RP patients were elevated .…”

“…These RP susceptibility genes identified thus far were involved in the DNA repair pathways, [7][8][9] oxidative stress pathways, 10 cellular signaling pathways, 11 and inflammatory response to ionizing radiation. [12][13][14] Surfactant protein D (SP-D), a component of lung surfactants, which reduces surface tension at the pulmonary air-liquid interface [15][16][17] and enhances defense against pathogens as the first line of innate pulmonary immunity, [18][19][20][21] has never been investigated with regard to the association between its genetic variants and the risk of RP. Previous study showed that serum levels of SP-D in RP patients were elevated.…”