Identification and Characterization of Zebrafish Tlr4 Coreceptor Md-2
| Autor: | Michael J. Harms, Melissa N. Hinman, Andrea N. Loes, Dylan R. Farnsworth, Karen Guillemin, Adam C. Miller |
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| Rok vydání: | 2021 |
| Předmět: |
Lipopolysaccharides
animal structures Immunology ved/biology.organism_classification_rank.species Lymphocyte Antigen 96 Danio Context (language use) Article Cell Line Mice 03 medical and health sciences 0302 clinical medicine Animals Humans Immunology and Allergy Model organism Zebrafish Gene Inflammation Mammals Innate immune system biology ved/biology Macrophages fungi NF-kappa B Zebrafish Proteins biology.organism_classification Immunity Innate Cell biology Toll-Like Receptor 4 HEK293 Cells TLR4 lipids (amino acids peptides and proteins) Amniote Signal Transduction 030215 immunology |
| Zdroj: | J Immunol |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | The zebrafish (Danio rerio) is a powerful model organism for studies of the innate immune system. One apparent difference between human and zebrafish innate immunity is the cellular machinery for LPS sensing. In amniotes, the protein complex formed by TLR4 and myeloid differentiation factor 2 (Tlr4/Md-2) recognizes the bacterial molecule LPS and triggers an inflammatory response. It is believed that zebrafish have neither Md-2 nor Tlr4; Md-2 has not been identified outside of amniotes, whereas the zebrafish tlr4 genes appear to be paralogs, not orthologs, of amniote TLR4s. We revisited these conclusions. We identified a zebrafish gene encoding Md-2, ly96. Using single-cell RNA sequencing, we found that ly96 is transcribed in cells that also transcribe genes diagnostic for innate immune cells, including the zebrafish tlr4-like genes. In larval zebrafish, ly96 is expressed in a small number of macrophage-like cells. In a functional assay, zebrafish Md-2 and Tlr4ba form a complex that activates NF-κB signaling in response to LPS. In larval zebrafish ly96 loss-of-function mutations perturbed LPS-induced cytokine production but gave little protection against LPS toxicity. Finally, by analyzing the genomic context of tlr4 genes in 11 jawed vertebrates, we found that tlr4 arose prior to the divergence of teleosts and tetrapods. Thus, an LPS-sensitive Tlr4/Md-2 complex is likely an ancestral feature shared by mammals and zebrafish, rather than a de novo invention on the tetrapod lineage. We hypothesize that zebrafish retain an ancestral, low-sensitivity Tlr4/Md-2 complex that confers LPS responsiveness to a specific subset of innate immune cells. |
| Databáze: | OpenAIRE |
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