SP-A2 contributes to miRNA-mediated sex differences in response to oxidative stress: pro-inflammatory, anti-apoptotic, and anti-oxidant pathways are involved

Abstract

BackgroundHuman innate host defense molecules, surfactant protein A1 (SP-A1), and SP-A2 differentially affect the function and proteome of the alveolar macrophage (AM). We hypothesized that SP-A genes differentially regulate the AM miRNome.MethodsHumanized transgenic mice expressing SP-A1 and SP-A2 were subjected to O3-induced oxidative stress (OxS) or filtered air (FA), AMs were isolated, and miRNA levels were measured.ResultsIn SP-A2 males, we found significant changes in miRNome in terms of sex and sex-OxS effects, with 11 miRNAs differentially expressed under OxS. Their mRNA targets included BCL2, CAT, FOXO1, IL6, NF-kB, SOD2, and STAT3. We followed the expression of these transcripts as well as key cytokines, and we found that (a) the STAT3 mRNA significantly increased at 4 h post OxS and returned to baseline at 18 h post OxS. (b) The anti-oxidant protein SOD2 level significantly increased, but the CAT level did not change after 4 h post OxS compared to control. (c) The anti-apoptotic BCL2 mRNA increased significantly (18 h post OxS), but the levels of the other transcripts were decreased. The presence of the SP-A2 gene had a protective role in apoptosis of AMs under OxS compared to mice lacking SP-A (knockout, KO). (d) Pro-inflammatory cytokine IL-6 protein levels were significantly increased in SP-A2 mice compared to KO (4 and 18 h post OxS), which signifies the role of SP-A2 in pro-inflammatory protein expression. (e) SOD2 and CAT mRNAs changed significantly in OxS indicating a plausible role of SP-A2 in the homeostasis of reactive oxygen species. (f) Gonadectomy of transgenic mice showed that sex hormones contribute to significant changes of the miRNome expression.ConclusionsWe conclude that SP-A2 influences the miRNA-mediated sex-specific differences in response to OxS. In males, these differences pertain to inflammatory, anti-apoptotic, and anti-oxidant pathways.Electronic supplementary materialThe online version of this article (10.1186/s13293-017-0158-2) contains supplementary material, which is available to authorized users.

Surfactant protein A and D polymorphisms and methylprednisolone pharmacogenetics in donor lungs

“…SP-A2 was recently shown to regulate microRNA, which we speculate could in turn regulate the SP-A and SP-D expression. 33 The results derived from the human donor PCLS model were different from the findings using the human lung cancer cell model with an SP-A1/SP-A2 genotype 6A 4 6A 4 /1A 5 1A 5 . The cell line showed a significant reduction of SP-A expression when methylprednisolone was used at high doses (Figure 1), but this was not observed at low doses.…”

Donor surfactant protein A2 polymorphism and lung transplant survival

“…Recent animal studies have shown that not only SP-A1 and SP-A2 variants distinctively affect the alveolar macrophage miRNome [25], but most relevantly they also differentially affect lung function and survival after infection [26,27]. It is therefore conceivable that SP-A gene variants may contribute to the complex etiologic pathogenesis of lung allograft dysfunction.…”

Using toponomics to characterize phenotypic diversity in alveolar macrophages from male mice treated with exogenous SP-A1

“…In humans, however, unlike in rodents, there are two genes, Sftpa1 and Sftpa2, encoding SP-A1 and SP-A2, respectively, and these two gene products have been shown to have a differential impact on several AM functions. These functions include bacterial phagocytosis and cytokine production by AM [18,24,25], actin polymerization in the AM [7], and effects on the AM proteome and miRNome [26][27][28]. Moreover, the effects of SP-A variants on the regulation of the AM proteome and miRNome, survival, and pulmonary mechanics after infection, vary with sex [26][27][28][29][30].…”