Serotonergic Chemosensory Neurons Modify the Immune Response by Regulating G-Protein Signaling in Epithelial Cells


The nervous and immune systems influence each other, allowing animals to rapidly protect themselves from changes in their internal and external environment. However, the complex nature of these systems in mammals makes it difficult to determine how neuronal signaling influences the immune response. Here we show that serotonin, synthesized in Caenorhabditis elegans chemosensory neurons, modulates the immune response. Serotonin released from these cells acts, directly or indirectly, to regulate G-protein signaling in epithelial cells. Signaling in these cells is required for the immune response to infection by the natural pathogen Microbacterium nematophilum. Here we show that serotonin signaling suppresses the innate immune response and limits the rate of pathogen clearance. We show that C. elegans uses classical neurotransmitters to alter the immune response. Serotonin released from sensory neurons may function to modify the immune system in response to changes in the animal's external environment such as the availability, or quality, of food.


Vyšlo v časopise: Serotonergic Chemosensory Neurons Modify the Immune Response by Regulating G-Protein Signaling in Epithelial Cells. PLoS Pathog 9(12): e32767. doi:10.1371/journal.ppat.1003787
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003787

Souhrn

The nervous and immune systems influence each other, allowing animals to rapidly protect themselves from changes in their internal and external environment. However, the complex nature of these systems in mammals makes it difficult to determine how neuronal signaling influences the immune response. Here we show that serotonin, synthesized in Caenorhabditis elegans chemosensory neurons, modulates the immune response. Serotonin released from these cells acts, directly or indirectly, to regulate G-protein signaling in epithelial cells. Signaling in these cells is required for the immune response to infection by the natural pathogen Microbacterium nematophilum. Here we show that serotonin signaling suppresses the innate immune response and limits the rate of pathogen clearance. We show that C. elegans uses classical neurotransmitters to alter the immune response. Serotonin released from sensory neurons may function to modify the immune system in response to changes in the animal's external environment such as the availability, or quality, of food.


Zdroje

1. SerafeimA, GordonJ (2001) The immune system gets nervous. Current Opinion in Pharmacology 1: 398–403.

2. GlaserR, Kiecolt-GlaserJK (2005) Stress-induced immune dysfunction: implications for health. Nat Rev Immunol 5: 243–251 doi:10.1038/nri1571

3. Gravato-NobreM, HodgkinJ (2005) Caenorhabditis elegans as a model for innate immunity to pathogens. Cell Microbiol 7: 741–792.

4. KawliT, TanM (2008) Neuroendocrine signals modulate the innate immunity of Caenorhabditis elegans through insulin signaling. Nat Immunol doi:10.1038/ni.1672

5. ShiversR, KooistraT, ChuS, PaganoD, KimD (2009) Tissue-specific activities of an immune signaling module regulate physiological responses to pathogenic and nutritional bacteria in C. elegans. Cell Host Microbe 6: 321–351.

6. ZhangY, LuH, BargmannCI (2005) Pathogenic bacteria induce aversive olfactory learning in Caenorhabditis elegans. Nat Cell Biol 438: 179–184 doi:10.1038/nature04216

7. ZugastiO, EwbankJJ (2009) Neuroimmune regulation of antimicrobial peptide expression by a noncanonical TGF-β signaling pathway in Caenorhabditis elegans epidermis. Nat Immunol 10: 249–256 doi:10.1038/ni.1700

8. PradelE, ZhangY, PujolN, MatsuyamaT, BargmannCI, et al. (2007) Detection and avoidance of a natural product from the pathogenic bacterium Serratia marcescens by Caenorhabditis elegans. Proc Natl Acad Sci USA 104: 2295–2300 doi:10.1073/pnas.0610281104

9. YookK, HodgkinJ (2007) Mos1 mutagenesis reveals a diversity of mechanisms affecting response of Caenorhabditis elegans to the bacterial pathogen Microbacterium nematophilum. Genetics 175: 681–697 doi:10.1534/genetics.106.060087

10. EvansEA, KawliT, TanM-W (2008) Pseudomonas aeruginosa Suppresses Host Immunity by Activating the DAF-2 Insulin-Like Signaling Pathway in Caenorhabditis elegans. PLoS Pathog 4: e1000175 doi:10.1371/journal.ppat.1000175

11. BrogdenKA, GuthmillerJM, SalzetM, ZasloffM (2005) The nervous system and innate immunity: the neuropeptide connection. Nat Immunol 6: 558–564 doi:10.1038/ni1209

12. SunJ, SinghV, Kajino-SakamotoR, AballayA (2011) Neuronal GPCR controls innate immunity by regulating noncanonical unfolded protein response genes. Science 332: 729–732 doi:10.1126/science.1203411

13. LeviteM (2012) The 1st International Meeting on Nerve-Driven Immunity: Neurotransmitters and Neuropeptides in the Immune System. Future Neurology 7: 247–253.

14. AhernGP (2011) 5-HT and the immune system. Current Opinion in Pharmacology doi:10.1016/j.coph.2011.02.004

15. BaganzNL, BlakelyRD (2013) A dialogue between the immune system and brain, spoken in the language of serotonin. ACS Chem Neurosci 4: 48–63 doi:10.1021/cn300186b

16. IrwinMM, LacherUU, CaldwellCC (1992) Depression and reduced natural killer cytotoxicity: a longitudinal study of depressed patients and control subjects. Psychol Med 22: 1045–1050 doi:10.1017/S0033291700038617

17. FrankMG, HendricksSE, JohnsonDR, WieselerJ, BurkeWJ (1999) Antidepressants Augment Natural Killer Cell Activity: In vivo and in vitro. Neuropsychobiology 39: 18–24 doi:10.1159/000026555

18. IdzkoM, PantherE, StratzC, MüllerT, BayerH, et al. (2004) The serotoninergic receptors of human dendritic cells: identification and coupling to cytokine release. J Immunol 172: 6011–6019.

19. MikulskiZ, ZaslonaZ, CakarovaL, HartmannP, WilhelmJ, et al. (2010) Serotonin activates murine alveolar macrophages through 5-HT2C receptors. Am J Physiol Lung Cell Mol Physiol 299: L272–L280 doi:10.1152/ajplung.00032.2010

20. Kushnir-SukhovNM, GilfillanAM, ColemanJW, BrownJM, BrueningS, et al. (2006) 5-hydroxytryptamine induces mast cell adhesion and migration. J Immunol 177: 6422–6432.

21. IkenK, ChhengS, FarginA, GouletA-C, KouassiE (1995) Serotonin Upregulates Mitogen-Stimulated B Lymphocyte Proliferation through 5-HT1AReceptors. Cellular Immunology 163: 1–9 doi:10.1006/cimm.1995.1092

22. HernandezME, Martinez-FongD, Perez-TapiaM, Estrada-GarciaI, Estrada-ParraS, et al. (2010) Evaluation of the effect of selective serotonin-reuptake inhibitors on lymphocyte subsets in patients with a major depressive disorder. European Neuropsychopharmacology 20: 88–95 doi:10.1016/j.euroneuro.2009.11.005

23. M R YoungJPM (1995) Serotonin regulation of T-cell subpopulations and of macrophage accessory function. Immunology 84: 148.

24. BoehmeSAS, LioFMF, SikoraLL, PanditTST, LavradorKK, et al. (2004) Cutting edge: serotonin is a chemotactic factor for eosinophils and functions additively with eotaxin. J Immunol 173: 3599–3603.

25. NowakEC, de VriesVC, WasiukA, AhonenC, BennettKA, et al. (2012) Tryptophan hydroxylase-1 regulates immune tolerance and inflammation. J Exp Med 209: 2127–2135 doi:10.1084/jem.20120408

26. WaltherDJ, PeterJ-U, BashammakhS, HörtnaglH, VoitsM, et al. (2003) Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299: 76–76 doi:10.1126/science.1078197

27. SzeJ, VictorM, LoerC, ShiY, RuvkunG (2000) Food and metabolic signalling defects in a Caenorhabditis elegans serotonin-synthesis mutant. Nature 403: 560–564.

28. SawinE, RanganathanR, HorvitzH (2000) C. elegans locomotory rate is modulated by the environment through a dopaminergic pathway and by experience through a serotonergic pathway. Neuron 26: 619–650.

29. AveryL, HorvitzHR (1990) Effects of starvation and neuroactive drugs on feeding in Caenorhabditis elegans. J Exp Zool 253: 263–270 doi:10.1002/jez.1402530305

30. SégalatL, ElkesD, KaplanJ (1995) Modulation of serotonin-controlled behaviors by Go in Caenorhabditis elegans. Science 267: 1648–1651 doi:10.1126/science.7886454

31. WaggonerL, ZhouG, SchaferR, SchaferW (1998) Control of alternative behavioral states by serotonin in Caenorhabditis elegans. Neuron 21: 203–217.

32. WeinshenkerD, GarrigaG, ThomasJH (1995) Genetic and pharmacological analysis of neurotransmitters controlling egg laying in C. elegans. J Neurosci 15: 6975–6985.

33. HodgkinJ, KuwabaraPE, CorneliussenB (2000) A novel bacterial pathogen, Microbacterium nematophilum, induces morphological change in the nematode C. elegans. Curr Biol 10: 1615–1618.

34. O'RourkeD, BabanD, DemidovaM, MottR, HodgkinJ (2006) Genomic clusters, putative pathogen recognition molecules, and antimicrobial genes are induced by infection of C. elegans with M. nematophilum. Genome Res 16: 1005–1016 doi:10.1101/gr.50823006

35. NicholasH, HodgkinJ (2004) The ERK MAP kinase cascade mediates tail swelling and a protective response to rectal infection in C. elegans. Curr Biol 14: 1256–1317.

36. McMullanR, AndersonA, NurrishS (2012) Behavioral and Immune Responses to Infection Require Gαq- RhoA Signaling in C. elegans. PLoS Pathog 8: e1002530 doi:10.1371/journal.ppat.1002530

37. JohnsonAD, FitzsimmonsD, HagmanJ, ChamberlinHM (2001) EGL-38 Pax regulates the ovo-related gene lin-48 during Caenorhabditis elegans organ development. Development 128: 2857–2865.

38. ChaoMY, KomatsuH, FukutoHS, DionneHM, HartAC (2004) Feeding status and serotonin rapidly and reversibly modulate a Caenorhabditis elegans chemosensory circuit. Proc Natl Acad Sci USA 101: 15512–15517 doi:10.1073/pnas.0403369101

39. SchulenburgH, EwbankJJ (2007) The genetics of pathogen avoidance in Caenorhabditis elegans. Mol Microbiol 66: 563–570 doi:10.1111/j.1365-2958.2007.05946.x

40. FlavellSW, PokalaN, MacoskoEZ, AlbrechtDR, LarschJ, et al. (2013) Serotonin and the Neuropeptide PDF Initiate and Extend Opposing Behavioral States in C. elegans. Cell 154: 1023–1035 doi:10.1016/j.cell.2013.08.001

41. ZhengX, ChungS, TanabeT, SzeJ (2005) Cell-type specific regulation of serotonergic identity by the C. elegans LIM-homeodomain factor LIM-4. Dev Biol 286: 618–646.

42. AspöckGG, RuvkunGG, BürglinTRT (2003) The Caenorhabditis elegans ems class homeobox gene ceh-2 is required for M3 pharynx motoneuron function. Development 130: 3369–3378 doi:10.1242/dev.00551

43. EstevezM, EstevezAO, CowieRH, GardnerKL (2003) The voltage-gated calcium channel UNC-2 is involved in stress-mediated regulation of tryptophan hydroxylase. J Neurochem 88: 102–113 doi:10.1046/j.1471-4159.2003.02140.x

44. RanganathanR, CannonSC, HorvitzHR (2000) MOD-1 is a serotonin-gated chloride channel that modulates locomotory behaviour in C. elegans. Nature 408: 470–475 doi:10.1038/35044083

45. HobsonRJR, HapiakVMV, XiaoHH, BuehrerKLK, KomunieckiPRP, et al. (2006) SER-7, a Caenorhabditis elegans 5-HT7-like receptor, is essential for the 5-HT stimulation of pharyngeal pumping and egg laying. Genetics 172: 159–169 doi:10.1534/genetics.105.044495

46. Carre-PierratM, BaillieD, JohnsenR, HydeR, HartA, et al. (2006) Characterization of the Caenorhabditis elegans G protein-coupled serotonin receptors. Invert Neurosci 6: 189–205 doi:10.1007/s10158-006-0033-z

47. NurrishS, SégalatL, KaplanJM (1999) Serotonin inhibition of synaptic transmission: Galpha(0) decreases the abundance of UNC-13 at release sites. Neuron 24: 231–242.

48. KoelleMR, HorvitzHR (1996) EGL-10 regulates G protein signaling in the C. elegans nervous system and shares a conserved domain with many mammalian proteins. Cell 84: 115–125 doi:10.1016/S0092-8674(00)80998-8

49. TengY, GirardL, FerreiraHB, SternbergPW, EmmonsSW (2004) Dissection of cis-regulatory elements in the C. elegans Hox gene egl-5 promoter. Dev Biol 276: 476–492 doi:10.1016/j.ydbio.2004.09.012

50. MendelJ, KorswagenH, LiuK, Hajdu-CroninY, SimonM, et al. (1995) Participation of the protein Go in multiple aspects of behavior in C. elegans. Science 267: 1652–1655 doi:10.1126/science.7886455

51. LacknerM, NurrishS, KaplanJ (1999) Facilitation of synaptic transmission by EGL-30 Gqalpha and EGL-8 PLCbeta: DAG binding to UNC-13 is required to stimulate acetylcholine release. Neuron 24: 335–381.

52. MILLERK (1999) Goα and Diacylglycerol Kinase Negatively Regulate the Gqα Pathway in C. elegans. Neuron 24: 323–333 doi:10.1016/S0896-6273(00)80847-8

53. HorvitzHR, ChalfieM, TrentC, SulstonJE, EvansPD (1982) Serotonin and octopamine in the nematode Caenorhabditis elegans. Science 216: 1012–1014.

54. JafariG, XieY, KullyevA, LiangB, SzeJY (2011) Regulation of Extrasynaptic 5-HT by Serotonin Reuptake Transporter Function in 5-HT-Absorbing Neurons Underscores Adaptation Behavior in Caenorhabditis elegans. J Neurosci 31: 8948–8957 doi:10.1523/JNEUROSCI.1692-11.2011

55. Hall DH, Altun ZF (2008) C. elegans atlas. Cold Spring Harbor Laboratory Press. 1 pp.

56. QinYY, ZhangXX, ZhangYY (2013) A neuronal signaling pathway of CaMKII and Gqα regulates experience-dependent transcription of tph-1. J Neurosci 33: 925–935 doi:10.1523/JNEUROSCI.2355-12.2013

57. BuninMAM, WightmanRMR (1998) Quantitative evaluation of 5-hydroxytryptamine (serotonin) neuronal release and uptake: an investigation of extrasynaptic transmission. J Neurosci 18: 4854–4860.

58. FarajBAB, OlkowskiZLZ, JacksonRTR (1994) Expression of a high-affinity serotonin transporter in human lymphocytes. Int J Immunopharmacol 16: 561–567 doi:10.1016/0192-0561(94)90107-4

59. GürelG, GustafsonMA, PepperJS, HorvitzHR, KoelleMR (2012) Receptors and Other Signaling Proteins Required for Serotonin Control of Locomotion in Caenorhabditis elegans. Genetics doi:10.1534/genetics.112.142125

60. McMullanR, NurrishS (2007) Rho deep in thought. Genes Dev 21: 2677–2759.

61. Hajdu-CroninYMY, ChenWJW, PatikoglouGG, KoelleMRM, SternbergPWP (1999) Antagonism between G(o)alpha and G(q)alpha in Caenorhabditis elegans: the RGS protein EAT-16 is necessary for G(o)alpha signaling and regulates G(q)alpha activity. Genes Dev 13: 1780–1793.

62. LuckiI (1998) The spectrum of behaviors influenced by serotonin. Biological psychiatry 44: 151–162.

63. ChuganiDC (2002) Role of altered brain serotonin mechanisms in autism. Mol Psychiatry 7: S16–S17 doi:10.1038/sj.mp.4001167

64. RodríguezJJ, NoristaniHN, VerkhratskyA (2012) The serotonergic system in ageing and Alzheimer's disease. Prog Neurobiol 99: 15–41 doi:10.1016/j.pneurobio.2012.06.010

65. SmithRS (1991) The macrophage theory of depression. Med Hypotheses 35: 298–306.

66. BrennerS (1974) The genetics of Caenorhabditis elegans. Genetics 77: 71–94.

67. AkimkinaT, YookK, CurnockS, HodgkinJ (2006) Genome characterization, analysis of virulence and transformation of Microbacterium nematophilum, a coryneform pathogen of the nematode Caenorhabditis elegans. FEMS Microbiol Lett 264: 145–196.

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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