1. Immunology and Inflammation
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Cytokines: A gut response

  1. Matthew L Nicotra  Is a corresponding author
  1. University of Pittsburgh, United States
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Cite this article as: eLife 2017;6:e28152 doi: 10.7554/eLife.28152


Unexpected findings from the immune system of sea urchin larvae potentially provide insights into immune signaling in ancestral animals.

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In 1882, Elie Metchnikoff peered through a microscope at a starfish larva and observed migrating cells engulf a splinter. He named these cells ‘phagocytes’, and they inspired the idea that certain cells defend the organism by eating foreign invaders (Metchnikoff, 1893). Metchnikoff’s phagocytosis theory described a new dimension of immunity and earned him a Nobel prize in 1908 (Tauber, 2003).

Starfish are echinoderms – a set of marine animals that also includes sea urchins. Nearly 100 years after Metchnikoff identified phagocytes, a team of scientists sequenced the urchin genome and made a startling discovery: several families of innate immune molecules had more than 200 members, which was much greater than anything encountered in previously sequenced animal genomes (Sea Urchin Genome Sequencing Consortium et al., 2006). As the genomes of additional species were sequenced, a picture emerged indicating that innate immune systems of echinoderms and other invertebrates rely on a genomic complexity not seen in mammals.

Encoded in the genome of many animals are molecules called cytokines that play important signaling roles in the immune system. Now, in eLife, Jonathan Rast, Katherine Buckley and co-workers at the University of Toronto and Sunnybrook Research Institute – including Buckley and Eric Ho as joint first authors – report unexpected results regarding a cytokine called IL-17 in echinoderm larvae (Buckley et al., 2017).

Immunologists focus a lot of attention on how cytokines control immune cells, but they (the cytokines, not the immunologists) can also work on other cell types. For example, in mice and humans, IL-17 acts almost entirely on the epithelial cells that line body cavities and the mesenchymal cells that make up connective tissue. In response to IL-17, the cells trigger inflammation – an important part of the early immune response (Amatya et al., 2017).

While Buckley et al. did not set out to study IL-17, they were interested in how urchins deal with bacteria in their guts. Urchin larvae feed by filtering microbe-rich seawater, and should therefore have robust gut immune responses. The larvae are transparent, which allowed Buckley et al. to watch as the same cell types that enthralled Metchnikoff engulfed bacteria in the gut. Yet even before the infection was visible, immune cells migrated to the gut and the gut epithelium thickened and closed off. This indicated an early, systemic immune response. Further investigation revealed that the urchin versions of IL-17 were some of the most highly expressed genes immediately after an infection. This raised the question of whether IL-17 has an ancient role as a regulator of gut microbial responses.

For most cytokines it would be difficult, if not impossible, to find the answer. Cytokines evolve so quickly that it is hard to identify which are homologs (i.e. which genes share a common ancestor). IL-17, however, has several highly conserved motifs that allowed Buckley et al. to identify 35 members of the IL-17 family in urchins. By contrast, mice and humans only have six members (Amatya et al., 2017). These 35 cytokines cluster into ten subgroups, dubbed SpIL17-1 through SpIL17-10. Remarkably, the subgroups appear in four other echinoderm species that span over 260 million years of evolution. This conservation suggests each family has a distinct and essential role. Unfortunately, more than 500 million years of evolution separates echinoderms and mammals, which prevents us from establishing the evolutionary relationships between individual urchin and mammalian genes, even for IL-17.

Buckley et al. next assembled a detailed picture of IL-17 expression in both adult urchins and larvae. All IL-17s were completely inactive in healthy larvae, but four hours after an infection the activity of two families – SpIL17-1 and SpIL17-4 – dramatically increased. Subsequently, several other immune genes were activated, including two hallmarks of inflammation. A series of cellular localization experiments further demonstrated that gut epithelial cells – and not immune cells – express IL-17 cytokines. Buckley et al. then combined publicly available data with their own experiments to show that in adult urchins, SpIL17-1 and SpIL17-4 are inactive during bacterial infections. Instead, a different family (SpIL17-9) increases its activity, which is followed by the expression of several echinoderm-specific defense molecules.

With 35 IL-17-like cytokines in the genome, one might expect a similar diversity of IL-17 receptors. However, Buckley et al. found only two. Blocking the translation of one of the receptor types was lethal for the larvae. Blocking the other receptor – termed IL-17R1 – reduced the expression of several (but not all) immune response genes, and did not prevent immune cell migration. Other pathways of immune activation must therefore exist.

These findings raise a number of questions. Why do echinoderms have ten IL-17 families yet apparently only two receptors? Do additional IL-17 receptors that lack homology to their vertebrate counterparts exist? How does the gut epithelium sense bacteria to trigger an immune response? One can expect that recent demonstrations of CRISPR/Cas9 mediated genome editing in urchins will help researchers to seek answers to these questions (Lin and Su, 2016).

More fundamentally, does the production of IL-17 by epithelial cells represent an ancestral immune state in animals? The answer could be yes. Nearly everything we know about mammalian IL-17 signaling comes from studies of a subfamily called IL-17A, which is secreted by immune cells, but several other IL-17s are produced by gut epithelial cells (Song et al., 2011).

In summary, these results reinforce the idea that we should study host immune defenses across the animal tree in order to discover general properties of immune systems (Litman and Cooper, 2007). Buckley et al. have achieved this by peering into an echinoderm. Metchnikoff would approve.


  1. 1
  2. 2
  3. 3
  4. 4
  5. 5
    Lectures on the Comparative Pathology of Inflammation
    1. E Metchnikoff
    London: Kegan Paul, Trench, Trubner, and Co, Ltd.
  6. 6
    The genome of the sea urchin Strongylocentrotus purpuratus
    1. Sea Urchin Genome Sequencing Consortium
    2. E Sodergren
    3. GM Weinstock
    4. EH Davidson
    5. RA Cameron
    6. RA Gibbs
    7. RC Angerer
    8. LM Angerer
    9. MI Arnone
    10. DR Burgess
    11. RD Burke
    12. JA Coffman
    13. M Dean
    14. MR Elphick
    15. CA Ettensohn
    16. KR Foltz
    17. A Hamdoun
    18. RO Hynes
    19. WH Klein
    20. W Marzluff
    21. DR McClay
    22. RL Morris
    23. A Mushegian
    24. JP Rast
    25. LC Smith
    26. MC Thorndyke
    27. VD Vacquier
    28. GM Wessel
    29. G Wray
    30. L Zhang
    31. CG Elsik
    32. O Ermolaeva
    33. W Hlavina
    34. G Hofmann
    35. P Kitts
    36. MJ Landrum
    37. AJ Mackey
    38. D Maglott
    39. G Panopoulou
    40. AJ Poustka
    41. K Pruitt
    42. V Sapojnikov
    43. X Song
    44. A Souvorov
    45. V Solovyev
    46. Z Wei
    47. CA Whittaker
    48. K Worley
    49. KJ Durbin
    50. Y Shen
    51. O Fedrigo
    52. D Garfield
    53. R Haygood
    54. A Primus
    55. R Satija
    56. T Severson
    57. ML Gonzalez-Garay
    58. AR Jackson
    59. A Milosavljevic
    60. M Tong
    61. CE Killian
    62. BT Livingston
    63. FH Wilt
    64. N Adams
    65. R Bellé
    66. S Carbonneau
    67. R Cheung
    68. P Cormier
    69. B Cosson
    70. J Croce
    71. A Fernandez-Guerra
    72. AM Genevière
    73. M Goel
    74. H Kelkar
    75. J Morales
    76. O Mulner-Lorillon
    77. AJ Robertson
    78. JV Goldstone
    79. B Cole
    80. D Epel
    81. B Gold
    82. ME Hahn
    83. M Howard-Ashby
    84. M Scally
    85. JJ Stegeman
    86. EL Allgood
    87. J Cool
    88. KM Judkins
    89. SS McCafferty
    90. AM Musante
    91. RA Obar
    92. AP Rawson
    93. BJ Rossetti
    94. IR Gibbons
    95. MP Hoffman
    96. A Leone
    97. S Istrail
    98. SC Materna
    99. MP Samanta
    100. V Stolc
    101. W Tongprasit
    102. Q Tu
    103. KF Bergeron
    104. BP Brandhorst
    105. J Whittle
    106. K Berney
    107. DJ Bottjer
    108. C Calestani
    109. K Peterson
    110. E Chow
    111. QA Yuan
    112. E Elhaik
    113. D Graur
    114. JT Reese
    115. I Bosdet
    116. S Heesun
    117. MA Marra
    118. J Schein
    119. MK Anderson
    120. V Brockton
    121. KM Buckley
    122. AH Cohen
    123. SD Fugmann
    124. T Hibino
    125. M Loza-Coll
    126. AJ Majeske
    127. C Messier
    128. SV Nair
    129. Z Pancer
    130. DP Terwilliger
    131. C Agca
    132. E Arboleda
    133. N Chen
    134. AM Churcher
    135. F Hallböök
    136. GW Humphrey
    137. MM Idris
    138. T Kiyama
    139. S Liang
    140. D Mellott
    141. X Mu
    142. G Murray
    143. RP Olinski
    144. F Raible
    145. M Rowe
    146. JS Taylor
    147. K Tessmar-Raible
    148. D Wang
    149. KH Wilson
    150. S Yaguchi
    151. T Gaasterland
    152. BE Galindo
    153. HJ Gunaratne
    154. C Juliano
    155. M Kinukawa
    156. GW Moy
    157. AT Neill
    158. M Nomura
    159. M Raisch
    160. A Reade
    161. MM Roux
    162. JL Song
    163. YH Su
    164. IK Townley
    165. E Voronina
    166. JL Wong
    167. G Amore
    168. M Branno
    169. ER Brown
    170. V Cavalieri
    171. V Duboc
    172. L Duloquin
    173. C Flytzanis
    174. C Gache
    175. F Lapraz
    176. T Lepage
    177. A Locascio
    178. P Martinez
    179. G Matassi
    180. V Matranga
    181. R Range
    182. F Rizzo
    183. E Röttinger
    184. W Beane
    185. C Bradham
    186. C Byrum
    187. T Glenn
    188. S Hussain
    189. G Manning
    190. E Miranda
    191. R Thomason
    192. K Walton
    193. A Wikramanayke
    194. SY Wu
    195. R Xu
    196. CT Brown
    197. L Chen
    198. RF Gray
    199. PY Lee
    200. J Nam
    201. P Oliveri
    202. J Smith
    203. D Muzny
    204. S Bell
    205. J Chacko
    206. A Cree
    207. S Curry
    208. C Davis
    209. H Dinh
    210. S Dugan-Rocha
    211. J Fowler
    212. R Gill
    213. C Hamilton
    214. J Hernandez
    215. S Hines
    216. J Hume
    217. L Jackson
    218. A Jolivet
    219. C Kovar
    220. S Lee
    221. L Lewis
    222. G Miner
    223. M Morgan
    224. LV Nazareth
    225. G Okwuonu
    226. D Parker
    227. LL Pu
    228. R Thorn
    229. R Wright
    Science 314:941–952.
  7. 7
  8. 8

Article and author information

Author details

  1. Matthew L Nicotra

    Thomas E. Starzl Transplant Institute and the Departments of Surgery and Immunology, University of Pittsburgh, Pittsburgh, United States
    For correspondence
    Competing interests
    The author declares that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5361-8398

Publication history

  1. Version of Record published: June 2, 2017 (version 1)


© 2017, Nicotra

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


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Further reading

  1. The sea urchin may be a good model for understanding how immune responses work in humans and other vertebrates.

    1. Cell Biology
    2. Immunology and Inflammation
    Leonie Zeitler et al.
    Research Article

    Interleukin-4-induced-1 (IL4i1) is an amino acid oxidase secreted from immune cells. Recent observations have suggested that IL4i1 is pro-tumorigenic via unknown mechanisms. As IL4i1 has homologues in snake venoms (LAAO, L-amino acid oxidases), we used comparative approaches to gain insight into the mechanistic basis of how conserved amino acid oxidases regulate cell fate and function. Using mammalian expressed recombinant proteins, we found venom LAAO kills cells via hydrogen peroxide generation. By contrast, mammalian IL4i1 is non-cytotoxic and instead elicits a cell productive gene expression program inhibiting ferroptotic redox death by generating indole-3-pyruvate (I3P) from tryptophan. I3P suppresses ferroptosis by direct free radical scavenging and through the activation of an anti-oxidative gene expression program. Thus, the pro-tumor effects of IL4i1 are likely mediated by local anti-ferroptotic pathways via aromatic amino acid metabolism, arguing that an IL4i1 inhibitor may modulate tumor cell death pathways.