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Sex differences in the acute in vivo effects of different human SP-A variants on the mouse alveolar macrophage proteome.

ABSTRACT: Surfactant protein A (SP-A) is involved in lung innate immunity. Humans have two SP-A genes, SFTPA1 and SFTPA2, each with several variants. We examined the in vivo effects of treatment with specific SP-A variants on the alveolar macrophage (AM) proteome from SP-A knockout (KO) mice. KO mice received either SP-A1, SP-A2, or both. AM were collected and their proteomes examined with 2D-DIGE. We identified 90 proteins and categorized them as related to actin/cytoskeleton, oxidative stress, protease balance/chaperones, regulation of inflammation, and regulatory/developmental processes. SP-A1 and SP-A2 had different effects on the AM proteome and these effects differed between sexes. In males more changes occurred in the oxidative stress, protease/chaperones, and inflammation groups with SP-A2 treatment than with SP-A1. In females most SP-A1-induced changes were in the actin/cytoskeletal and oxidative stress groups. We conclude that after acute SP-A1 and SP-A2 treatment, sex-specific differences were observed in the AM proteomes from KO mice, and that these sex differences differ in response to SP-A1 and SP-A2. Females are more responsive to SP-A1, whereas the gene-specific differences in males were minimal. These observations not only demonstrate the therapeutic potential of exogenous SP-A, but also illustrate sex- and gene-specific differences in the response to it.This study shows that changes occur in the alveolar macrophage proteome in response to a single in vivo treatment with exogenous SP-A1 and/or SP-A2. We demonstrate that SP-A1 and SP-A2 have different effects on the AM proteome and that sex differences exist in the response to each SP-A1 and SP-A2 gene product. This study illustrates the potential of exogenous SP-A1 and SP-A2 treatment for the manipulation of macrophage function and indicates that the specific SP-A variant used for treatment may vary with sex and with the cellular functions being modified. The observed changes may contribute to sex differences in the incidence of some lung diseases.

SUBMITTER: Phelps DS

PROVIDER: S-EPMC4128237 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Sex differences in the acute in vivo effects of different human SP-A variants on the mouse alveolar macrophage proteome.

Phelps David S DS Umstead Todd M TM Floros Joanna J

Journal of proteomics 20140618

Surfactant protein A (SP-A) is involved in lung innate immunity. Humans have two SP-A genes, SFTPA1 and SFTPA2, each with several variants. We examined the in vivo effects of treatment with specific SP-A variants on the alveolar macrophage (AM) proteome from SP-A knockout (KO) mice. KO mice received either SP-A1, SP-A2, or both. AM were collected and their proteomes examined with 2D-DIGE. We identified 90 proteins and categorized them as related to actin/cytoskeleton, oxidative stress, protease ...[more]

PMID: 24954098

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Project description:UnlabelledBackgroundMale wild type (WT) C57BL/6 mice are less capable of clearing bacteria and surviving from bacterial pneumonia than females. However, if an oxidative stress (acute ozone exposure) occurs before infection, the advantage shifts to males who then survive at higher rates than females. We have previously demonstrated that survival in surfactant protein-A (SP-A) knockout (KO) mice compared to WT was significantly reduced. Because the alveolar macrophage (AM) is pivotal in host defense we hypothesized that SP-A and circulating sex hormones are responsible for these sex differences. We used 2D-DIGE to examine the relationship of sex and SP-A on the AM proteome. The role of SP-A was investigated by treating SP-A KO mice with exogenous SP-A for 6 and 18 hr and studying its effects on the AM proteome.ResultsWe found: 1) less variance between KO males and females than between the WT counterparts by principal component analysis, indicating that SP-A plays a role in sex differences; 2) fewer changes in females when the total numbers of significantly changing protein spots or identified whole proteins in WT or 18 hr SP-A-treated males or females were compared to their respective KO groups; 3) more proteins with functions related to chaperones or protease balance and Nrf2-regulated proteins changed in response to SP-A in females than in males; and 4) the overall pattern of SP-A induced changes in actin-related proteins were similar in both sexes, although males had more significant changes.ConclusionsAlthough there seems to be an interaction between sex and the effect of SP-A, it is unclear what the responsible mechanisms are. However, we found that several of the proteins that were expressed at significantly higher levels in females than in males in WT and/or in KO mice are known to interact with the estrogen receptor and may thus play a role in the SP-A/sex interaction. These include major vault protein, chaperonin subunit 2 (beta) (CCT2), and Rho GDP alpha dissociation inhibitor. We conclude that sex differences exist in the proteome of AM derived from male and female mice and that SP-A contributes to these sex differences.

Project description:Monocyte derived macrophages (MDMs) infiltrate sites of infection or injury and upregulate cyclooxygenase-2 (COX-2), an enzyme that stimulates prostaglandin-E2 (PgE2). Nanotheranostics combine therapeutic and diagnostic agents into a single nanosystem. In previous studies, we demonstrated that a nanotheranostic strategy, based on theranostic nanoemulsions (NE) loaded with a COX-2 inhibitor (celecoxib, CXB) and equipped with near-infrared fluorescent (NIRF) reporters, can specifically target circulating monocytes and MDMs. The anti-inflammatory and anti-nociceptive effects of such cell-specific COX-2 inhibition lasted several days following Complete Freund's Adjuvant (CFA) or nerve injury in male mice. The overall goal of this study was to investigate the extended (up to 40 days) impact of MDM-targeted COX-2 inhibition and any sex-based differences in treatment response; both of which remain unknown. Our study also evaluates the feasibility and efficacy of a preclinical nanotheranostic strategy for mechanistic investigation of the impact of such sex differences on clinical outcomes. Methods: CFA was administered into the right hind paws of male and female mice. All mice received a single intravenous dose of NIRF labeled CXB loaded NE twelve hours prior to CFA injection. In vivo whole body NIRF imaging and mechanical hypersensitivity assays were performed sequentially and ex vivo NIRF imaging and immunohistopathology of foot pad tissues were performed at the end point of 40 days. Results: Targeted COX-2 inhibition of MDMs in male and female mice successfully improved mechanical hypersensitivity after CFA injury. However, we observed distinct sex-specific differences in the intensity or longevity of the nociceptive responses. In males, a single dose of CXB-NE administered via tail vein injection produced significant improved mechanical hypersensitivity for 32 days as compared to the drug free NE (DF-NE) (untreated) control group. In females, CXB-NE produced similar, though less prominent and shorter-lived effects, lasting up to 11 days. NIRF imaging confirmed that CXB-NE can be detected up to day 40 in the CFA injected foot pad tissues of both sexes. There were distinct signal distribution trends between males and females, suggesting differences in macrophage infiltration dynamics between the sexes. This may also relate to differences in macrophage turnover rate between the sexes, a possibility that requires further investigation in this model. Conclusions: For the first time, this study provides unique insight into MDM dynamics and the early as well as longer-term targeted effects and efficacy of a clinically translatable nanotheranostic agent on MDM mediated inflammation. Our data supports the potential of nanotheranostics as presented in elucidating the kinetics, dynamics and sex-based differences in the adaptive or innate immune responses to inflammatory triggers. Taken together, our study findings lead us closer to true personalized, sex-specific pain nanomedicine for a wide range of inflammatory diseases.

Dataset Information

Sex differences in the acute in vivo effects of different human SP-A variants on the mouse alveolar macrophage proteome.

Publications

Sex differences in the acute in vivo effects of different human SP-A variants on the mouse alveolar macrophage proteome.

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