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IL-17 is a neuromodulator of Caenorhabditis elegans sensory responses

Nature volume 542, pages 43–48 (2017)Cite this article

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Abstract

Interleukin-17 (IL-17) is a major pro-inflammatory cytokine: it mediates responses to pathogens or tissue damage, and drives autoimmune diseases. Little is known about its role in the nervous system. Here we show that IL-17 has neuromodulator-like properties in Caenorhabditis elegans. IL-17 can act directly on neurons to alter their response properties and contribution to behaviour. Using unbiased genetic screens, we delineate an IL-17 signalling pathway and show that it acts in the RMG hub interneurons. Disrupting IL-17 signalling reduces RMG responsiveness to input from oxygen sensors, and renders sustained escape from 21% oxygen transient and contingent on additional stimuli. Over-activating IL-17 receptors abnormally heightens responses to 21% oxygen in RMG neurons and whole animals. IL-17 deficiency can be bypassed by optogenetic stimulation of RMG. Inducing IL-17 expression in adults can rescue mutant defects within 6 h. These findings reveal a non-immunological role of IL-17 modulating circuit function and behaviour.

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Figure 1: IL-17 promotes aggregation and escape from 21% O2.
Figure 2: Anatomical focus of ILC-17.1 signalling.
Figure 3: ILC-17.1 signalling alters RMG physiology.
Figure 4: Overexpressing ILC-17.1 heightens responsiveness to 21% O2.
Figure 5: ACTL-1, PIK-1/IRAK, and NFKI-1 mediate ILC-17.1 signalling in RMG.

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Acknowledgements

We thank the Caenorhabditis Genetics Center (funded by National Institutes of Health Infrastructure Program P40 OD010440) and the Japanese knockout consortium for strains, J. Hadfield and the Cambridge Research Institute Genomics Core for whole genome sequencing, Z. Soltesz for software, B. Gyenes for help screening for mutants, S. Flynn for help with mapping, and de Bono laboratory members for comments on the manuscript. This work was supported by a European Molecular Biology Organization Fellowship (to C.C.), a Japan Society for the Promotion of Science Post-doctoral Fellowship (to E.I.), the Medical Research Council, UK, and the European Research Council (Advanced Grant 269058) to M.d.B.

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Author notes

  1. Eisuke Itakura & Patrick Laurent

    Present address: †Present addresses: Department of Nanobiology, Graduate School of Advanced Integration Science, Chiba University, Chiba, 263-8522, Japan (E.I.); Université Libre de Bruxelles, Laboratory of Neurophysiology, Campus Erasme, 808 Route de Lennik, 1070 Bruxelles, Belgium (P.L.).,

Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK

    Changchun Chen, Eisuke Itakura, Geoffrey M. Nelson, Ming Sheng, Patrick Laurent, Lorenz A. Fenk, Ramanujan S. Hegde & Mario de Bono

  2. Department of Chemistry, University of Florida, Gainesville, 32611, Florida, USA

    Rebecca A. Butcher

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Contributions

C.C., E.I., R.S.H., and M.d.B. designed experiments. C.C., E.I., M.S., P.L., and L.A.F. performed experiments. G.N. did the genome sequence data analysis. R.A.B. provided reagents. C.C., E.I., R.S.H., and M.d.B. analysed the data. C.C. and M.d.B. wrote the paper.

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Correspondence to Mario de Bono.

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The authors declare no competing financial interests.

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Reviewer Information Nature thanks R. Garcia, O. Hobert and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data figures and tables

Extended Data Figure 1 Interleukin-17-related proteins and receptors in C. elegans.

a, Schematic of the exon/intron structures of the Y64G10A.6 (ilcr-1), F56D1.2 (ilcr-2), and T22H6.1 (ilc-17.1) genes, with the location of mutations used in assays indicated. The terms -1 FS and -7 FS denote frameshift mutations with 1 and 7 base pair deletions. Other alleles are shown in Extended Data Table 1. b, Schematic showing the bordering and aggregation assay. The number of animals on the edge of the food lawn, or in groups, was counted 24 h after animals were transferred to the assay plates. c, Bordering and aggregation phenotypes of single-, double-, and triple-null mutants of ilc-17.1, ilcr-1, and ilcr-2; n = 4 assays; ***P < 0.001, ANOVA with Tukey correction. d, CRISPR induced mutations in the F56D1.2 (ilcr-2) gene, and the F25D1.3 and C44B12.6 genes, which show homology to mammalian IL-17. e, Bordering and aggregation assays for the F25D1.3 and C44B12.6 mutants; n = 4 assays. NS, not significant (ANOVA with Tukey correction). f, Alignment of the SEFIR domains of IL-17 receptors, including C. elegans ILCR-1 and ILCR-2. g, Alignment of IL-17D proteins with ILC-17.1. Arrowheads indicate conserved cysteine residues. h, ILC-17.1 forms disulfide-linked dimers. SDS–PAGE of affinity-purified Flag–ILC-17.1 boiled in sample buffer with or without 100 mM DTT. i, The O2 response defects of ilc-17.1 and ilcr-1 mutants are rescued by Mos1-mediated single copy insertion (MosSCI) of ilc-17.1 and ilcr-1 transgenes; n = 4 assays, 120 animals. ***P < 0.001, Mann–Whitney U-test. j, The O2 response defects of ilc-17.1, ilcr-1, and nfki-1 double mutants with the natural npr-1 215F allele; n = 4 assays, 120 animals. ***P < 0.001, Mann–Whitney U-test.

Extended Data Figure 2 ILC-17.1 signalling in RMG promotes aggregation and escape from 21% O2.

a, b, The bordering and aggregation defects of ilcr-1 and ilcr-2 mutants can be rescued by selectively expressing their cDNAs in RMG interneurons (pnpr-1 and pflp-5). Bordering but not aggregation is partly rescued by expression in the O2-sensing neurons URX, AQR, and PQR (pgcy-32); n = 4 assays. *P < 0.05, **P < 0.01, ****P < 0.0001, ANOVA with Tukey correction. c, d, O2 responses of ilcr-1 (c) and ilcr-2 (d) mutants expressing the corresponding cDNA selectively in RMG (pnpr-1 and pflp-5), the O2 sensing neurons URX, AQR, and PQR (pgcy-32), or the ASE gustatory neurons (pflp-6); n = 4 assays, 120 animals. ***P < 0.001, Mann–Whitney U-test. e, Expressing ilcr-1 or pik-1 cDNA in ASG neurons, using the ops-1 promoter, fails to rescue the O2 response defects of the corresponding mutants; n = 4 assays, 120 animals. ***P < 0.001, Mann–Whitney U-test. f, Expressing ilcr-1 cDNA in cholinergic neurons (punc-17 or pacr-2), GABAergic neurons (punc-25), or interneurons controlling forward and reverse movement (pglr-1, pnmr-1) fails to restore sustained locomotory arousal to ilcr-1 mutants kept at 21% O2; n = 4 assays, 120 animals. ***P < 0.001, Mann–Whitney U-test. g, Expressing ilc-17.1 cDNA in RMG using the flp-5 promoter rescues defective responses to 21% O2 in ilc-17.1 mutants. Speed assays were performed 2 h after animals were transferred to the assay plates; n = 4 assays, 120 animals. ***P < 0.001, Mann–Whitney U-test. h, Expressing ilc-17.1 cDNA from the odr-10 promoter (AWA) or the flp-6 promoter (ASE) not only rescues the ilc-17.1 defect but confers abnormally heightened escape from 21% O2; n = 4 assays, 120 animals. **P < 0.01, ***P < 0.001, Mann–Whitney U-test. i, Expressing ilcr-2 cDNA using the flp-5 promoter rescues the RMG O2-evoked Ca2+ responses defects of ilcr-2 mutants. ***P < 0.001, Mann–Whitney U-test. The npr-1 control is the same as in Fig. 4e. j, The ilc-17.1; npr-1 215F and nfki-1; npr-1 215F mutants show defective O2-evoked Ca2+ response in RMG; npr-1 215F is the allele found in natural isolates of C. elegans. ***P < 0.001, Mann–Whitney U-test. k, Expression of pflp-5::GFP in RMG interneurons, a reporter of RMG neurosecretory activity, is reduced in ilc-17.1, ilcr-1, and ilcr-2 mutants. ***P < 0.001, ANOVA with Tukey correction. l, m, The ilc-17.1, pik-1, and nfki-1 mutants display normal chemotaxis to NaCl (l) and benzaldehyde (m); n = 6 assays. NS, not significant, ANOVA with Tukey correction. n, Ca2+ responses evoked in AIB interneurons by benzaldehyde (1:10,000 dilution) are normal in ilc-17.1 mutants; bz, benzaldehyde; Mann–Whitney U-test.

Extended Data Figure 3 Heat-shock-induced expression of ILCR-1 and ILCR-2 in adults rescues behavioural defects of corresponding mutants.

a–d, Transgenic adults expressing ilcr-1 cDNA (a, b) or ilcr-2 cDNA (c, d) from the hsp-16.41 promoter were assayed either without heat-shock (a, c) or after 30 min of heat-shock (b, d). The assays in b and d were performed 8 h after the heat-shock; n = 4 assays, 120 animals. **P < 0.01, ***P < 0.001, NS, not significant, Mann–Whitney U-test.

Extended Data Figure 4 Timeline of heat-shock-induced rescue of ilc-17.1 after 15- and 30-min heat shocks.

a, The ilc-17.1 mutants expressing ilc-17.1 cDNA from the hsp-16.41 promoter assayed without heat shock. Assays were performed 2 h after animals were picked to assay plates; n = 4 assays, 120 animals. ***P < 0.001, Mann–Whitney U-test. b, c, Timelines showing mCherry expression (b) and speed at 21% O2 (c) of ilc-17.1 mutants bearing a phsp-16.41::ilc-17.1::mCherry bicistronic transgene and heat shocked for 15 or 30 min. For each mCherry measurement, n = 24; speed in c is the average of a 1-min time window, 40 s after switching to 21% O2 and 20 s before switching back to 7% O2, indicated with a red bar in d and e. The dashed lines in c indicate the average speed of npr-1 (black) and ilc-17.1 npr-1 (blue) animals for comparison. **P < 0.01, ***P < 0.001, Mann–Whitney U-test; P values in black are for comparisons with npr-1 control; P values in blue are for comparisons with ilc-17.1 npr-1 controls. d, e, Transgenic animals expressing ilc-17.1 cDNA from the hsp-16.41 promoter were exposed to 34 °C for 15 min (d) or 30 min (e), then assayed every 2 h. Statistical comparisons between npr-1 and transgenic animals with heat-shock constructs are indicated in orange. Comparisons between npr-1 ilc-17.1 and transgenic animals with heat-shock constructs are indicated in black; n = 4 assays, 120 animals. ***P < 0.001, **P < 0.01, *P < 0.05, Mann–Whitney U-test.

Extended Data Figure 5 Overexpressing ILC-17.1 stimulates flp-5 neuropeptide expression in RMG.

a, b, Overexpressing ilc-17.1 stimulates expression from the pflp-5::GFP reporter in RMG both in N2 (a) and npr-1 (b) animals. Conversely, disrupting ilc-17.1 reduces pflp-5::gfp expression. **P < 0.01, ***P < 0.001, Mann–Whitney U-test.

Extended Data Figure 6 Phenotypes of C. elegans homologues of mammalian genes involved in inflammatory responses.

a, b, Speed was assayed 10 min (a) and 2 h (b) after animals were transferred to the assay plates; n = 4 assays, 120 animals. NS, not significant, Mann–Whitney U-test.

Extended Data Figure 7 The C. elegans Act1-like gene.

a, b, The actl-1 alleles. Allele db789 was isolated in strain AX3544 after mutagenesis using ethylmethanesulfonate (EMS) (a); db1202 and db1203 are frameshift mutations generated by CRISPR (b). c, Mos1-mediated single-copy insertion (MosSCI) of the actl-1, pik-1, and nfki-1 genes rescues the O2 response defects of the corresponding mutants; n = 4 assays, 120 animals. ***P < 0.001, **P < 0.01, Mann–Whitney U-test. d, A null mutation in actl-1 confers ilc-17.1-like responses to 21% O2, and does not show additive phenotypes with ilc-17.1 or pik-1 null mutations; n = 4 assays, 120 animals. ***P < 0.001, Mann–Whitney U-test. e, Domain architecture of ACTL-1, showing the locations of the Death and SEFIR domains. f, Alignment of the SEFIR domains of ACT1 and ACT1-like proteins. C. elegans ACTL-1 is shown at the top.

Extended Data Figure 8 Disrupting pik-1/IRAK causes ilc-17.1-like phenotypes.

a, Schematic of the exon/intron structure of pik-1, highlighting the db842 and tm2167 mutations used in this study. The allele db842 was found in strain AX3604; tm2167 was obtained from the Japanese knockout consortium. b, The pik-1 mutants exhibit an ilc-17.1-like defect and fail to sustain rapid movement at 21% O2. The pik-1 and ilc-17.1 phenotypes are non-additive, suggesting the proteins encoded by these genes act in the same pathway; n = 4 assays, 120 animals. **P < 0.01, Mann–Whitney U-test. c, The bordering and aggregation defects of pik-1 mutants can be rescued by expressing pik-1 cDNA from the pik-1 or flp-5 promoters (RMG); n = 4 assays. ***P < 0.001, ****P < 0.0001, Mann–Whitney U-test. d, A functional ppik-1::pik-1::SL2::mCherry polycistronic transgene is expressed broadly in the nervous system. RMG expression was confirmed using a pflp-5::gfp fiduciary marker. e, f, Sustained rapid movement of ilc-17.1 overexpressing animals at 21% O2 is blocked by mutations in the pik-1 gene. Speed assays were performed 10 min (e) and 2 h (f) after picking animals to the assay plates; n = 4 assays, 120 animals. ***P < 0.001, Mann–Whitney U-test.

Extended Data Figure 9 Mutations in the nfki-1 gene cause ilc-17.1-like phenotypes.

a, b, The nfki-1 alleles. Allele db923 in strain AX3677 was obtained in an EMS screen (a); the db1198 frameshift mutation was generated using CRISPR (b). c, A functional pnfki-1::nfki-1::SL2::mCherry polycistronic transgene is expressed broadly in the nervous system. RMG expression was confirmed using a pflp-5::gfp fiduciary marker. d, e, Phenotypes of nfki-1, pik-1, and ilc-17.1 molecular null alleles are not additive; n = 4 assays, 120 animals. ***P < 0.001, Mann–Whitney U-test. f, Schematic of the human IκBζ b isoform and NFKI-1, highlighting ankyrin repeats (ANK). g, Alignment of amino-acid sequences for IκBζ orthologues from different species. NFKI-1 is shown at the bottom. Conserved residues are highlighted.

Extended Data Table 1 Mutations in IL-17 signalling components identified by forward genetics
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This file contains a Supplementary Figure and Supplementary Table 1. The Supplementary Figure shows the raw data for Figures 1c and 5 a, b, c, d and the Supplementary Table contains the strain list. (PDF 488 kb)

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Chen, C., Itakura, E., Nelson, G. et al. IL-17 is a neuromodulator of Caenorhabditis elegans sensory responses. Nature 542, 43–48 (2017). https://doi.org/10.1038/nature20818

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