Differential Sex-Dependent Regulation of the Alveolar Macrophage miRNome of SP-A2 and co-ex (SP-A1/SP-A2) and Sex Differences Attenuation after 18 h of Ozone Exposure

Abstract

Background: Human SP-A1 and SP-A2, encoded by SFTPA1 and SFTPA2, and their genetic variants differentially impact alveolar macrophage (AM) functions and regulation, including the miRNome. We investigated whether miRNome differences previously observed between AM from SP-A2 and SP-A1/SP-A2 mice are due to continued qualitative differences or a delayed response of mice carrying a single gene. Methods: Human transgenic (hTG) mice, carrying SP-A2 or both SP-A genes, and SP-A-KO mice were exposed to filtered air (FA) or ozone (O3). AM miRNA levels, target gene expression, and pathways determined 18 h after O3 exposure. RESULTS: We found (a) differences in miRNome due to sex, SP-A genotype, and exposure; (b) miRNome of both sexes was largely downregulated by O3, and co-ex had fewer changed (≥2-fold) miRNAs than either group; (c) the number and direction of the expression of genes with significant changes in males and females in co-ex are almost the opposite of those in SP-A2; (d) the same pathways were found in the studied groups; and (e) O3 exposure attenuated sex differences with a higher number of genotype-dependent and genotype-independent miRNAs common in both sexes after O3 exposure. Conclusion: Qualitative differences between SP-A2 and co-ex persist 18 h post-O3, and O3 attenuates sex differences.

Surfactant Protein A (SP-A)1 And SP-A2 Differentially Affect F-Actin Levels in The Alveolar Macrophage

“…Of interest the bacterial phagocytic index was measured 1hr after infection, a time shown previously to associate with a decrease in F-actin levels and increase in cell area [11] and changes in cell size are also depicted here in Figure 1A. Furthermore, the NF-κB and Nrf2 pathways and/or proteins involved in these pathways have been shown to be differentially affected by SP-A1 and SP-A2 under different conditions [20,30] and these, in turn, may regulate the AM response to oxidative stress [16][17][18][19]31] and/or inflammatory processes [28,29].…”

“…These have been shown to differentially affect the bacterial phagocytic activity of AMs, with SP-A2 exhibiting a significantly higher activity than SP-A1 [4,14,15]. Differences between SP-A1 and SP-A2 have been observed in several AM processes [16][17][18][19][20][21][22], including in actin cytoskeleton, as assessed by single cell analysis [23] and in proteomics where the SP-A1 and SP-A2 heat maps of actin-related/ cytoskeleton proteins differed [20]. In this communication we studied further the differential effect of SP-A1 and SP-A2 on AM F-actin by using phalloidin fluorescence measurements, Western blot analysis of centrifugally separated cell fractions and mining proteomics data.…”

Human Surfactant Protein SP-A1 and SP-A2 Variants Differentially Affect the Alveolar Microenvironment, Surfactant Structure, Regulation and Function of the Alveolar Macrophage, and Animal and Human Survival Under Various Conditions

“…The SP-A2 males showed overall similarities with the co-ex males where there was largely a downregulation of the miRNome and upregulation of the target genes (117,123). Moreover, differences in the AM miRNome and their target genes between co-ex and SP-A2 male and female mice persists even at 18hr post O 3 exposure, with O 3 exposure shown to attenuate sex differences (125). At this time point the overall pathways were similar but the direction and the number of changed miRNAs in response to O 3 varied, indicating underlying complexities in the mechanisms involved and an interplay of O 3 exposure, time of post exposure, sex, and SP-A genotype.…”

Surfactant Protein A and Microbiome Composition in Patients With Atraumatic Intraoral Lesions

“…During pulmonary development, SP-A expression is regulated by a complex array of factors including hormones [ 39 ]. Further, alveolar macrophage response to infection is regulated in a sex-specific manner by Sp-A during ozone exposure [ 40 – 42 ]. Our findings in the oral cavity microbiome demonstrate that oral SP-A contributes to the relative proportions of bacteria in the community, whether this is through opsonization and macrophage activation is unknown but worthy of further study.…”