Buckley KM and Rast JP (2017), An Organismal Model for Gene Regulatory Network...

ECB-ART-45849

Front Immunol 2017 Mar 13;8:1297. doi: 10.3389/fimmu.2017.01297.

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An Organismal Model for Gene Regulatory Networks in the Gut-Associated Immune Response.

Buckley KM , Rast JP .

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The gut epithelium is an ancient site of complex communication between the animal immune system and the microbial world. While elements of self-non-self receptors and effector mechanisms differ greatly among animal phyla, some aspects of recognition, regulation, and response are broadly conserved. A gene regulatory network (GRN) approach provides a means to investigate the nature of this conservation and divergence even as more peripheral functional details remain incompletely understood. The sea urchin embryo is an unparalleled experimental model for detangling the GRNs that govern embryonic development. By applying this theoretical framework to the free swimming, feeding larval stage of the purple sea urchin, it is possible to delineate the conserved regulatory circuitry that regulates the gut-associated immune response. This model provides a morphologically simple system in which to efficiently unravel regulatory connections that are phylogenetically relevant to immunity in vertebrates. Here, we review the organism-wide cellular and transcriptional immune response of the sea urchin larva. A large set of transcription factors and signal systems, including epithelial expression of interleukin 17 (IL17), are important mediators in the activation of the early gut-associated response. Many of these have homologs that are active in vertebrate immunity, while others are ancient in animals but absent in vertebrates or specific to echinoderms. This larval model provides a means to experimentally characterize immune function encoded in the sea urchin genome and the regulatory interconnections that control immune response and resolution across the tissues of the organism.

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Genes referenced: irak1bp1 LOC100887844 LOC105440996 LOC105444986 LOC115919910 LOC115925415 LOC575170 LOC583082

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Figure 1. Exposure to the marine bacterium Vibrio diazotrophicus induces an acute gut-associated inflammatory response in sea urchin larvae. (A,B) Sea urchin larvae exhibit a cellular immune response mediated by several mesodermally derived cell types. The mesenchyme blastula-stage embryo is shown from the vegetal view (A). In Strongylocentrotus purpuratus, embryos reach this stage about 24 hpf. The ring of non-skeletal mesoderm (NSM) cells is indicated by either red (aboral NSM) or blue (oral NSM). All other cell lineages are shown in gray. Aboral NSM cells differentiate into larval pigment cells; the oral NSM derivatives become the heterogeneous blastocoelar cells. Aboral and lateral views of the pluteus larvae are shown (B). Morphological features are indicated (pigment cells, blastocoelar cells, celomic pouches, skeleton, and gut). The images shown in panels (A,B) are not to scale. (C,D) Larvae mount a cellular and transcriptional immune response to exposure to V. diazotrophicus in the sea water. In the first 24â€‰h of exposure to V. diazotrophicus, the midgut epithelium thickens, reducing the volume of the gut lumen. Pigment cells change shape from a stellate to round morphology and migrate from the ectoderm to the gut. Cell motility increases, and complex cell:cell interactions occur. Bacteria begin to penetrate the gut epithelium and enter the epithelium, where they are phagocytosed by a subset of filopodial cells. One of the first transcriptional events is the acute upregulation of the IL17-1 genes in the gut epithelium. This is followed by activation of a second wave of immune gene upregulation, including the IL17-4 subtype. Immune effector genes, such as Trf, are activated in a subset of filopodial cells later in the response. Data are described in detail in Ref. (17, 29).

Figure 2. Interleukin 17 (IL17) signaling mediates the larval immune response. A hypothetical scheme of the signaling molecules and transcriptional events that occur during the initial phase of the larval gut-associated immune response is shown. The community of normal microbiota is shown within the gut lumen in shades of brown. The introduction of pathogenic bacteria (indicated in dark red) to the gut is sensed by receptors the gut epithelial cells as a microbial disturbance [indicated by step (1)]. A signaling cascade is initiated that results in the transcriptional upregulation of the IL17-1 genes [step (2)]. This is evident within 2â€‰h of seawater exposure to Vibrio diazotrophicus. IL17-1 protein (dark blue) is secreted, where it can interact with widely expressed IL17 receptors and affect gene expression in cells distributed across the organism. IL17-R1 and -R2 are shown here as heterodimers, although they may also homodimerize. Upon activation, these receptors initiate intracellular signaling pathways that result in the upregulation of an IL17-dependent gene battery [step (3); shown in the green box]. These genes were identified using in vivo perturbation of IL17-R1 signaling (29). Notably, this includes the IL17-4 gene, which is always activated subsequent to IL17-1. This linkage may point to regulatory feedback between the two subtypes and, given the rapid attenuation of IL17-1 transcripts, the IL17-4 protein (light blue) may serve as an inhibitory mechanism. Given the broad expression patterns of the IL17 receptors, it is likely that immune cells (blastocoelar cells are shown in blue; pigment cells, pink) contain cell-type specific regulatory circuitry that controls immune gene expression in response to IL17 signaling. Spliced messages from the other IL17 subtypes (gray) can be recovered from larvae, although the levels are very low. These may be activated under different immune challenge conditions.

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Aderem, Toll-like receptors in the induction of the innate immune response. 2000, Pubmed