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Suppression of xenogeneic innate immune response by a membrane-type human surfactant protein-A.

ABSTRACT: Macrophage-mediated xenogeneic rejection is a major immunological obstacle. We recently reported that membrane-type surfactant protein-D (SP-D) on swine endothelial cells (SECs) suppressed macrophage-mediated rejection. Similar to SP-D, the carbohydrate recognition domain of surfactant protein-A (SP-A) can induce inhibitory signals in effector cells. The present study aimed to examine the suppressive effect of SP-A on macrophage-mediated xenogeneic rejection. Naive SECs and SPA-transfected SECs (SEC/SP-A) were co-cultured with THP-1 cells and cytotoxicity was evaluated. To investigate the effect of SP-A on phagocytosis, human macrophages were co-cultured with SEC or SEC/SP-A, and the extent of phagocytosis and production of reactive oxygen species were assessed via flow cytometry. The mRNA expression levels of inflammatory cytokines in macrophages were determined using reverse transcription-PCR. Additionally, the effects of THP-1-Lucia NF-κB cells on transcription factors were evaluated. The cytotoxicity and phagocytosis of SEC/SP-A were significantly decreased compared with those of naive SEC. Furthermore, the co-culture of human macrophages with SEC/SP-A decreased reactive oxygen species production, and the mRNA expression levels of TNFα were decreased in macrophages, whereas those of IL-10 were increased. In addition, NF-κB transcription was decreased in SEC/SP-A compared with that in SEC. In conclusion, the ectopic expression of human SP-A in porcine cells represents an attractive method for suppressing macrophage-mediated cytotoxicity.

SUBMITTER: Toyama C

PROVIDER: S-EPMC9353545 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Suppression of xenogeneic innate immune response by a membrane-type human surfactant protein-A.

Toyama Chiyoshi C Maeda Akira A Kogata Shuhei S Yamamoto Riho R Masahata Kazunori K Ueno Takehisa T Kamiyama Masafumi M Tazuke Yuko Y Eguchi Hiroshi H Okuyama Hiroomi H Miyagawa Shuji S

Experimental and therapeutic medicine 20220726 3

Macrophage-mediated xenogeneic rejection is a major immunological obstacle. We recently reported that membrane-type surfactant protein-D (SP-D) on swine endothelial cells (SECs) suppressed macrophage-mediated rejection. Similar to SP-D, the carbohydrate recognition domain of surfactant protein-A (SP-A) can induce inhibitory signals in effector cells. The present study aimed to examine the suppressive effect of SP-A on macrophage-mediated xenogeneic rejection. Naive SECs and SPA-transfected SECs ...[more]

PMID: 35949334

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Project description:To combat infections, the mammalian host limits availability of essential transition metals such as iron (Fe), zinc (Zn), and manganese (Mn) in a strategy termed "nutritional immunity." The innate immune protein calprotectin (CP) contributes to nutritional immunity by sequestering these metals to exert antimicrobial activity against a broad range of microbial pathogens. One such pathogen is Pseudomonas aeruginosa, which causes opportunistic infections in vulnerable populations, including individuals with cystic fibrosis. CP was previously shown to withhold Fe(II) and Zn(II) from P. aeruginosa and induce Fe and Zn starvation responses in this pathogen. In this work, we performed quantitative, label-free proteomics to further elucidate how CP impacts metal homeostasis pathways in P. aeruginosa. We report that CP induces an incomplete Fe starvation response, as many Fe-containing proteins that are repressed by Fe limitation are not affected by CP treatment. The Zn starvation response elicited by CP seems to be more complete than the Fe starvation response and includes increases in Zn transporters and Zn-independent proteins. CP also induces the expression of membrane-modifying proteins, and metal depletion studies indicate this response results from the sequestration of multiple metals. Moreover, the increased expression of membrane-modifying enzymes upon CP treatment correlates with increased tolerance to polymyxin B. Thus, the response of P. aeruginosa to CP treatment includes both single- and multimetal starvation responses and includes many factors related to virulence potential, broadening our understanding of this pathogen's interaction with the host. IMPORTANCE Transition metal nutrients are critical for growth and infection by all pathogens, and the innate immune system withholds these metals from pathogens to limit their growth in a strategy termed "nutritional immunity." While multimetal depletion by the host is appreciated, the majority of studies have focused on individual metals. Here, we use the innate immune protein calprotectin (CP), which complexes with several metals, including iron (Fe), zinc (Zn), and manganese (Mn), and the opportunistic pathogen Pseudomonas aeruginosa to investigate multimetal starvation. Using an unbiased label-free proteomics approach, we demonstrate that multimetal withholding by CP induces a regulatory response that is not merely additive of individual metal starvation responses, including the induction of lipid A modification proteins.

Dataset Information

Suppression of xenogeneic innate immune response by a membrane-type human surfactant protein-A.

Publications

Suppression of xenogeneic innate immune response by a membrane-type human surfactant protein-A.

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