Full-length review
Invertebrate molecular neuroimmune processes

https://doi.org/10.1016/S0165-0173(00)00041-2Get rights and content

Abstract

During the course of evolution, invertbrates and vertebrates have kept in common similar signaling molecules e.g. neuropeptides, opiates etc… Complete hormonal–enzymatic systems such as the opioid–opiate–cannabinoid systems have been found in both nervous central and immune systems of these animals. These signaling molecules can be found free in blood circulation and act as immunomodulators. The present review is focused on peptides derived from the opioid proopiomelanocortin precursor, the opiates and the endocannabinoids, which are very powerful immunosuppressors, and example models of the bidirectional communications between the endocrine and the immune systems. Parasites use these immunosuppressors with magnificence in their crosstalk with their host.

Introduction

A new understanding gained in invertebrates as well as vertebrates, is that substances involved in chemical communication among immunoactive cells are the same, or closely related to those used in the bidirectional exchange of information between the immune system and the neuroendocrine apparatus [3], [4], [33], [68], [85], [86]. Recently, this concept has been expanded to include parasites since they also appear to use the same signal molecules to escape immunodetection [16], [44].

Stefano’s group demonstrates with Deltorphin I, a naturally occurring opioid peptide isolated from amphibian skin, the ability of this substance to modulate both human and invertebrate immunoregulatory activities in a manner quite similar to Met-enkephalin [69]. Its binding and pharmacological studies also have provided evidence for a special subtype of delta opioid receptor δ2, sensitive to naltrindole antagonist on human and invertebrate immune cells [66]. It is also of interest to note that both the invertebrate immunocytes and human granulocytes thus have a δ1 and δ2 receptor [66]. It is clear within the context of this review that host immunocytes having these receptors, and those to be mentioned below, have the potential to respond to similar peptides secreted by the parasite within the host body, thus effectively ‘taking’ over the local communication in their vicinity, without altering global host function.

Opiate alkaloids, e.g., morphine, deserve special attention within the context of this report for several reasons. First, unlike antinociceptive mechanisms, opiate alkaloids and opioid peptides initiate different immunocyte behaviors [66]. Opioid peptides may be generally regarded as immunocyte stimulatory and/or activating ligands whereas morphine, as first noted by Wybran et al. [87], is inhibitory [66]. Secondly, confusion exists in the scientific literature as to the proper terminology for these ligands, opioid alkaloid and opiate peptide. Thirdly a novel opiate alkaloid sensitive and opioid peptide insensitive receptor, namely μ3, has been demonstrated which does not recognize μ-opioid ligands [66]. Lastly, opiate alkaloids appear to be naturally occurring substances found both in mammals and invertebrates [24], [63], [66].

In this regard, the immunosuppressive effect of opiate material expresses itself in a lowering of chemotactic activity, cellular velocity and adherence as well as making active immunocytes inactive (rounded; [66]). These pharmacological effects of morphine on immunocytes are consistent with those actions attributed to opiates reported in the literature [66]. Indeed, it has been surmised that morphinergic transmission may regulate the downregulation of immune activation [66]. Recent studies demonstrate that human granulocytes also contain the μ3 subtype opiate receptor mediating inhibition by morphine and other opiates of cytokine-induced activation and chemotaxis [31]. The discovery of this receptor site mediating opiate effects were first found in an invertebrate and then in man, again demonstrating the value of the comparative approach [66], [73], [74]. This also suggested that these processes might be operational in parasites as well.

Proopiomelanocortin (POMC), i.e., adrenocorticotropin (ACTH) and β-endorphin (βE), is expressed in the cells of the immune system [5], [29], [30], [55], [56], [57]. These observations were then extended to mouse splenocytes [29], [30]. It was only in 1988 that the presence of a mRNA species hybridizing a POMC probe was demonstrated in human B and T lymphocytes [34]. The identity of the peptides produced in lymphocytes with those originally described in the pituitary was definitively shown in a very elegant study by Smith et al. [59]. These authors isolated and microsequenced ACTH produced by LPS-activated mouse splenocytes. The purified peptide was found to be identical to mouse ACTH 1–25. In the same study, reverse transcription of murine lymphocyte RNA, followed by a specific amplification of the POMC mRNA by polymerase chain reaction and sequence analysis, demonstrated the identity of pituitary and lymphocyte POMC mRNAs. This work constitutes the definitive demonstration of the transcription, translation and post-translational processing of POMC in cells of the immune system.

The presence of POMC derived peptides in spreading hemocytes from the snail Planorbarius corneus also has been demonstrated. In this animal, ACTH and βE appear to modulate chemotaxis and phagocytosis by these hemocytes [27], [36], [37]. ACTH-like molecules have also been identified in the marine mollusc M. edulis [59]. In this model, Stefano and co-workers [71], [79] have demonstrated that both α- and β-MSH can inactivate mollusc and insect hemocytes by inhibiting their motility. This was studied by a technique of computer-assisted analysis of cellular conformation. Using the same method, MSH was found to exert the same activity on human granulocytes and monocytes, in agreement with the results of Van Epps and coworkers [49], [68], [71], [82], [83].

Recently, Salzet, Stefano and co-workers in a series of reports [44], [45], [46], [47], [48], [49], [64], have demonstrated that heamatophagous invertebrates (leeches) contain the major opioid peptide precursors, i.e., prodynorphin, POMC and proenkephalin, that contain mammalian-like opioid peptides exhibiting high sequence identity with their mammalian counterparts. These studies corroborated the earlier works of Duvaux-Miret, Capron and co-workers [6], [7], [8], [9], [16], [17], [18], [19], suggesting that parasites may communicate with their hosts via common signaling molecules.

The above data also suggest that neuroimmune interactions emerged early in evolution. In this context, the question arises as to whether cytokines exist in invertebrates. Stefano and co-workers first demonstrated that cytokine-like molecules are synthesized in the nervous and immune systems of invertebrates, and that neuropeptides can regulate their production in both tissues [22], [23], [40], [72]. However, real proof from the molecular point of view has not been yet given in invertebrates. Some indirect evidence (immunological) has recently been provided [36]. Moreover, Hoek et al. [21] have found a new Ig superfamily member in the mollusc Lymnaea stagnalis. This molluscan defense protein is down regulated during parasitosis from Trichobilharzia ocellata. Furthermore, with the discovery in Drosophila of a receptor which is a mammalian homolog of the interleukin-1 type 1 receptor containing a highly conserved region in its cytosolic domain, so-called Toll [35], a novel receptor superfamily present in invertebrates and mammals, the IL-1R/toll-like receptor (TLR) superfamily has been defined.

In summary, there is today growing evidence that the nervous and the immune systems can exchange information, mainly through small molecules, either cytokines or neuropeptides. Furthermore, it appears that some so-called neurotransmitters like neuropeptides can function as endogenous messengers of the immune system, and that they most likely play an important part in the regulation of the various components of the immune response. Parasite infections are a very attractive model in immunology since the immune response fails to kill the parasite but still continues to function. We have been interested in the implications of neuroimmunology in models of host–parasite interactions.

Section snippets

Vascular neuroimmunology

An exciting new finding by Stefano et al. [78] demonstrates that the distribution of opiate receptors has been broadened to several cell types other than the nervous and immune systems. Based on the well-established hypotensive effect of morphine, they hypothesized in 1996 that endothelial cells may represent a target for this opiate substance. Endothelial cells (human arterial and rat microvascular) contain a high-affinity, saturable opiate binding site presumed to mediate the morphine

Neuroimmunology and parasitology

Most parasites share their life cycle between several hosts, these being vertebrates, insects or molluscs. It was therefore of interest to investigate the possible commonalities implied in the concept of neuroimmunology and autoimmunoregulation.

Parasitism implies a very precise equilibrium between the parasite and the various microenvironments where each stage of the life cycle takes place. In each biotope the parasite is able to achieve its survival, growth and/or maturation by using a whole

Conclusion

During the last 2 decades, a number of mammalian-like or identical signal molecules have been identified in different parasite species. The presence of POMC-like derived peptides (such like ACTH, a MSH or bE), morphine-like substances (codeine, morphine sulfate) or endocannabinoids (anandamide, 2 AG) in endo- and ecto-parasites demonstrates that the fields of neuroimmunology and parasitology overlap, highlighting the significance of these signal molecules in autoimmunoregulatory processes since

Acknowledgements

This work was in part supported by the Centre National de la Recherche Scientifique, FEDER, Conseil Regional Nord-Pas de Calais and the NIH Fogarty INT 00045 grant.

References (84)

  • L.A.J. O’Neill et al.

    The IL-1 receptor/toll-like receptor superfamily: crucial receptors for inflammation and host defense

    Immunol. Today

    (2000)
  • E. Ottaviani et al.

    The invertebrate phagocytic immunocyte: clues to a common evolution of immune and neuroendocrine systems

    Immunol. Today

    (1997)
  • E. Ottaviani et al.

    Presence of ACTH and β-endorphin immunoreactive molecules in the freshwater snail Planorbarius corneus (L.) (Gastropoda pulmonata) and their possible role in phagocytosis

    Regul. Pept.

    (1990)
  • E.J. Pearce et al.

    Functional dichotomy in CD4+T cell response to Schistosoma mansoni

    Exp. Parasitol.

    (1991)
  • B. Salzet et al.

    Putative leech dopamine1-like receptor molecular characterization: sequence homologies between dopamine and serotonin leech CNS receptors explain pharmacological cross-reactivities

    Mol. Brain Res.

    (1998)
  • M. Salzet et al.

    First biochemical evidence for an enzyme related to mammalian renin in an invertebrate the leech Theromyzon tessulatum

    Mol. Cell. Endocrinol.

    (1997)
  • M. Salzet et al.

    Isolation and biochemical characterization of proenkephalin from invertebrate immunocytes: δ-opioid binding sites in leech immunocytes

    Brain Res.

    (1997)
  • M. Salzet et al.

    Serpins: an evolutionarily conserved survival strategy

    Immunol. Today

    (1999)
  • B. Scharrer

    Neuroimmunology: the importance and role of a comparative approach

    Adv. Neuroimmunol.

    (1991)
  • M.A. Shipp et al.

    CD10 (CALLA)/Neutral endopeptidase 24.11 modulates inflammatory peptide-induced changes in neutrophil morphology, migration, and adhesion proteins and is itself regulated by neutrophil activation

    Blood

    (1991)
  • E.M. Smith et al.

    The production and action of ACTH-related peptides in invertebrate hemocytes

    Adv. Neuroimmunol.

    (1991)
  • D. Sonetti et al.

    Endogenous morphine levels increase in molluscan neural and immune tissues after physical trauma

    Brain Res.

    (1999)
  • G.B. Stefano et al.

    Leech CNS cannabinoid receptor is coupled to nitric oxide release: high sequence homology with mammals

    Brain Res.

    (1997)
  • G.B. Stefano

    Role of opioid neuropeptides in immunoregulation

    Prog. Neurobiol.

    (1989)
  • G.B. Stefano et al.

    Opioid induction of immunoreactive interleukin 1 in Mytilus edulis and human immunocytes: an interleukin1 like substance in invertebrate neural tissue

    J. Neuroimmunol.

    (1991)
  • G.B. Stefano et al.

    High affinity dopamine binding to mouse thymocytes and Mytilus edulis (Bivalvia) hemocytes

    J. Neuroimmunol.

    (1989)
  • G.B. Stefano et al.

    Effect of prolonged exposure to morphine on responsiveness of human and invertebrate immunocytes to stimulatory molecules

    J. Neuroimmunol.

    (1995)
  • C.J. Bayne et al.

    Determinants of compatibility in mollusc-trematode parasitism

    Am. Zool.

    (1989)
  • J.E. Blalock et al.

    A complete loop between the immune and neuroendocrine system

    Fed. Proc.

    (1985)
  • J.E. Blalock

    A molecular basis for bidirectional communication between the immune and neuroendocrine systems

    Physiol. Rev.

    (1989)
  • J.E. Blalock et al.

    Human leukocyte interferon: structure and biological relatedness to adrenocorticotropic hormone and endorphins

    Proc. Natl. Acad. Sci. USA

    (1980)
  • A. Capron et al.

    Le language moleculaire des parasites

    Med. Sci.

    (1995)
  • A. Capron et al.

    Molecular basis of host–parasite relationship: toward the definition of protective antigens

    Immunol. Rev.

    (1989)
  • A. Capron et al.

    Progress toward vaccine against schistosomiasis

  • A. Capron et al.

    Immunity towards schistosomes: progress toward vaccine

    Science

    (1987)
  • D.G. Deutsch et al.

    Production and physiological actions of anandamide in the vasculature of the rat kidney

    J. Clin. Invest.

    (1997)
  • C. Dissous et al.

    Schistosoma mansoni shares a protective oligosaccharide epitope with freshwater and marine snails

    Nature

    (1986)
  • O. Duvaux-Miret et al.

    Proopiomelanocortin in the helminth Schistosoma mansoni. Synthesis of β-endorphin, ACTH and α-MSH. Existence of POMC-related sequences

    Ann. NY Acad. Sci.

    (1992)
  • O. Duvaux-Miret et al.

    The helminth Schistosoma mansoni expresses a peptide similar to human β-endorphin and possesses a POMC-related gene

    New Biologist

    (1990)
  • O. Duvaux-Miret et al.

    Immunosuppression in the definitive and intermediate hosts of the human parasite Schistosoma mansoni by release of immunoactive neuropeptides

    Proc. Natl. Acad. Sci. USA

    (1992)
  • O. Duvaux-Miret et al.

    Proopiomelanocortin-derived peptides as tools of immune evasion for the human trematode Schistosoma mansoni

    Acta Biol. Hung.

    (1992)
  • J.M. Grzych et al.

    Egg deposition is the major stimulus for the production of Th2 cytokines in murine schistosomiasis

    J. Immunol.

    (1991)
  • Cited by (38)

    • C-terminal conserved motifs of Neprilysin1 in Cotesia plutellae are not required for immune suppression of the Diamondback moth, Plutella xylostella (L.)

      2019, Journal of Asia-Pacific Entomology
      Citation Excerpt :

      From the aspect of neuronal function as well as immune, NEP involves in immunoregulatory peptides process (Zhu et al., 2003), whose roles are commonly conserved in mammals (Turner et al., 2001). In the previous reports, when the egg accompanied with maternal factors was injected into the host, oxidative stress by increase of reactive oxygen species (ROS) induces adrenocorticotropin hormone (ACTH), α-melanocyte-stimulating hormone (α-MSH) and the reaction of NEP, resulting in the control of melanization (Ottaviani et al., 2012; Grimaldi et al., 2012; Salzet, 2000). Cp-NEP1 revealed immune-suppressive activity without biochemically important conserved motif such as HExxH, ExxxD and CxxW, suggesting that these motifs are not required for host immune suppression.

    • Evolution of the diacylglycerol lipases

      2016, Progress in Lipid Research
    • From models to mechanisms: Odorant communication as a key determinant of social behavior in rodents during illness-associated states

      2011, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      Specifically, parasite infection appears to modulate behavior only during the early phase of infection, not for the entire period of parasitation (Kavaliers et al., 1997; Elsen and DeNardo, 2000; Morales-Montor et al., 2001). Interestingly, parasites are able to produce immuno-modulatory molecules such as β-endorphin that decrease the immune response of the hosts (Salzet, 2000; Maizels et al., 2004). It should be noted also that many bacteria thrive (proliferate) in the presence of host-derived hormones such as epinephrine and norepinephrine, which, as described previously, are released during the acute phase of infection (Vlisidou et al., 2004; Freestone et al., 2008; Sandrini et al., 2010).

    • A putative endocrine factor SIBD (single insulin binding domain protein) involved in immune response of Chinese mitten crab Eriocheir sinensis

      2010, Fish and Shellfish Immunology
      Citation Excerpt :

      Primary study suggested that SIBD, as the same multiple roles observed in the vertebrate IGFBP7 [34–40], probably involved in both endocrine and immune response [16]. In fact, many vertebrate molecules were involved in both endocrine and immune system except for IGFBP7 [8,41–44]. For instance, classical hormones such as glucocorticoid (GC), prolactin (PRL) and growth hormone (GH) could be produced by cells of the immune system [44,45].

    View all citing articles on Scopus
    1

    Membre de l’Institut Universitaire de France.

    View full text