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Differential impact of co-expressed SP-A1/SP-A2 protein on AM miRNome; sex differences

ABSTRACT: In humans there are two surfactant protein A (SP-A) functional genes SFTPA1 and SFTPA2 encoding innate immune molecules, SP-A1 and SP-A2, respectively, with numerous genetic variants each. SP-A interacts and regulates many of the functions of alveolar macrophages (AM). It is shown that SP-A variants differ in their ability to regulate the AM miRNome in response to oxidative stress (OxS). Because humans have both SP-A gene products, we were interested to determine the combined effect of co-expressed SP-A1/SP-A2 (co-ex) in response to ozone (O3) induced OxS on AM miRNome. Human transgenic (hTG) mice, carrying both SP-A1/SP-A2 (6A2/1A0, co-ex) and SP-A- KO were utilized. The hTG and KO mice were exposed to filtered air (FA) or O3 and miRNA levels were measured after AM isolation with or without normalization to KO. We found: (i) The AM miRNome of co-ex males and females in response to OxS to be largely downregulated after normalization to KO, but after Bonferroni multiple comparison analysis only in females the AM miRNome remained significantly different compared to control (FA); (ii) The targets of the significantly changed miRNAs were downregulated in females and upregulated in males; (iii) Several of the validated mRNA targets were involved in pro-inflammatory response, anti-apoptosis, cell cycle, cellular growth and proliferation; (iv) The AM of SP-A2 male, shown, previously to have major effect on the male AM miRNome in response to OxS, shared similarities with the co-ex, namely in pathways involved in the pro-inflammatory response and anti-apoptosis but also exhibited differences with the cell-cycle, growth, and proliferation pathway being involved in co-ex and ROS homeostasis in SP-A2 male. We speculate that the presence of both gene products versus single gene products differentially impact the AM responses in males and females in response to OxS.

ORGANISM(S): Mus musculus

PROVIDER: GSE135233 | GEO | 2019/08/02

REPOSITORIES: GEO

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Project description:Surfactant protein A (SP-A) in addition to its surfactant-related functions interacts with alveolar macrophages (AM), the guardian cells of innate immunity, and regulates many of its functions under basal condition and in response to various insults, such as infection and oxidative stress. The human SP-A locus consists of two functional genes, SFTPA1 and SFTPA2, and one pseudogene. The functional genes encode human SP-A1 and SP-A2 proteins, respectively, and each has been shown to have several genetic variants. It has been shown that SP-A variants differ in their ability to regulate lung function mechanics and survival in response to bacterial infection. Here, we investigated the effect of hSP-A variants on the AM gene expression profile in response to K. pneumoniae (Kp) infection. We used four humanized transgenic (hTG) mice that each carried SP-A1 (6A2, 6A4) or SP-A2 (1A0, 1A3), and KO. The gene expression profiling of AM was performed after 6 h post-infection. We found: a) significant sex differences in the expression of AM genes between males and females; b) in response to infection, 858 (KO), 196 (6A2), 494 (6A4), 276 (1A0) and 397 (1A3) genes were identified (P < 0.05) and some of these were differentially expressed with ≥ 2 fold, specific to either males or females; c) significant gene-specific differences between the SP-A1 and SP-A2 variants; d) via Ingenuity Pathway Analysis (IPA) key pathways and molecules were identified that had direct interaction with TP53, TNF, and cell cycle signaling nodes; e) validation of key molecules exhibited significant differences in the expression between males and females; f) IPA for SP-A1 and SP-A2 variants and KO revealed, top diseases and bio-functions for males and females that contained a high number of genes involved in the inflammatory response, immunological disease, infectious diseases, respiratory diseases, cancer, and others. These results reveal for the first time a large number of biologically relevant functional pathways influenced by sex and SP-A variant in response to K. pneumoniae infection. These data may assist in studying molecular mechanisms of SP-A-mediated AM gene regulation and potentially identify novel therapeutic targets for K. pneumoniae infection.

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Differential impact of co-expressed SP-A1/SP-A2 protein on AM miRNome; sex differences

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