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LRRK2: An Emerging New Molecule in the Enteric Neuronal System That Quantitatively Regulates Neuronal Peptides and IgA in the Gut

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Abstract

Background

Leucine-rich repeat kinase 2 (LRRK2) is a recently discovered molecule associated with familial and sporadic Parkinson’s disease. It regulates many central neuronal functions such as cell proliferation, apoptosis, autophagy, and axonal extension. However, in contrast to the well-documented function of LRRK2 in central neurons, it is unclear whether LRRK2 is expressed in enteric neurons and affects the physiology of the gut.

Aims

By examining LRRK2-KO mice, this study investigated whether enteric neurons express LRRK2 and whether intestinal neuronal peptides and IgA are quantitatively changed.

Methods

Intestinal protein lysates and sections prepared from male C57BL/6 J mice were analyzed by Western blotting and immunostaining using anti-LRRK2 antibody, respectively. Intestinal neuronal peptide-mRNAs were quantified by real-time PCR in wild-type mice and LRRK2-KO mice. Intestinal IgA was quantified by ELISA. Lamina propria mononuclear cells (LPMCs) were analyzed by flow cytometry to evaluate the ratio of B1 to B2 B cells.

Results

Western analysis and immunostaining revealed that LRRK2 is expressed in enteric neurons. The amounts of mRNA for vasoactive intestinal peptide, neuropeptide Y, and substance P were increased in LRRK2-KO mice accompanied by an increment of IgA. However, the intestinal B cell subpopulations were not altered in LRRK2-KO mice.

Conclusions

For the first time, we have revealed that LRRK2 is expressed in enteric neurons and related to quantitative alterations of neuronal peptide and IgA. Our study highlights the importance of LRRK2 in enteric neurons as well as central neurons.

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References

  1. Funayama M, Hasegawa K, Kowa H, Saito M, Tsuji S, Obata F. A new locus for Parkinson’s disease (PARK8) maps to chromosome 12p11.2-q13.1. Ann Neurol. 2002;51:296–301.

    Article  CAS  PubMed  Google Scholar 

  2. Funayama M, Hasegawa K, Ohta E, et al. An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family. Ann Neurol. 2005;57:918–921.

    Article  CAS  PubMed  Google Scholar 

  3. Paisán-Ruíz C, Jain S, Evans EW, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron. 2004;44:595–600.

    Article  PubMed  Google Scholar 

  4. Barrett JC, Hansoul S, Nicolae DL, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn′s disease. Nat Genet. 2008;40:955–962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Franke A, McGovern DP, Barrett JC, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn′s disease susceptibility loci. Nat Genet. 2010;42:1118–1125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhang FR, Huang W, Chen SM, et al. Genomewide association study of leprosy. N Engl J Med. 2009;361:2609–2618.

    Article  CAS  PubMed  Google Scholar 

  7. Meylan E, Tschopp J. The RIP kinases: crucial integrators of cellular stress. Trends Biochem Sci. 2005;30:151–159.

    Article  CAS  PubMed  Google Scholar 

  8. Higashi S, Moore DJ, Colebrooke RE, et al. Expression and localization of Parkinson’s disease-associated leucine-rich repeat kinase 2 in the mouse brain. J Neurochem. 2007;100:368–381.

    Article  CAS  PubMed  Google Scholar 

  9. Liu Z, Lee J, Krummey S, Lu W, Cai H, Lenardo MJ. The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat Immunol. 2011;12:1063–1070.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kubo M, Kamiya Y, Nagashima R, et al. LRRK2 is expressed in B-2 but not in B-1 B cells, and downregulated by cellular activation. J Neuroimmunol. 2010;229:123–128.

    Article  CAS  PubMed  Google Scholar 

  11. Moehle MS, Webber PJ, Tse T, et al. LRRK2 inhibition attenuates microglial inflammatory responses. J Neurosci. 2012;32:1602–1611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hakimi M, Selvanantham T, Swinton E, et al. Parkinson’s disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures. J Neural Transm. 2011;118:795–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Esteves AR, Swerdlow RH, Cardoso SM. LRRK2, a puzzling protein: insights into Parkinson’s disease pathogenesis. Exp Neurol. 2014;261:206–216.

    Article  CAS  PubMed  Google Scholar 

  14. Martin I, Kim JW, Dawson VL, Dawson TM. LRRK2 pathobiology in Parkinson’s disease. J Neurochem. 2014;131:554–565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Furness JB. Types of neurons in the enteric nervous system. J Auton Nerv Syst. 2000;81:87–96.

    Article  CAS  PubMed  Google Scholar 

  16. Coelho-Aguiar Jde M, Bon-Frauches AC, Gomes AL, et al. The enteric glia: identity and functions. Glia. 2015;63:921–935.

    Article  PubMed  Google Scholar 

  17. Schemann M. Control of gastrointestinal motility by the “gut brain”—the enteric nervous system. J Pediatr Gastroenterol Nutr. 2005;41:S4–6.

    Article  PubMed  Google Scholar 

  18. Genton L, Kudsk KA. Interactions between the enteric nervous system and the immune system: role of neuropeptides and nutrition. Am J Surg. 2003;186:253–258.

    Article  CAS  PubMed  Google Scholar 

  19. Neunlist M, Van Landeghem L, Mahé MM, Derkinderen P, des Varannes SB, Rolli-Derkinderen M. The digestive neuronal-glial-epithelial unit: a new actor in gut health and disease. Nat Rev Gastroenterol Hepatol. 2013;10:90–100.

    Article  CAS  PubMed  Google Scholar 

  20. Vu JP, Million M, Larauche M, et al. Inhibition of vasoactive intestinal polypeptide (VIP) induces resistance to dextran sodium sulfate (DSS)-induced colitis in mice. J Mol Neurosci. 2014;52:37–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Margolis KG, Stevanovic K, Karamooz N, et al. Enteric neuronal density contributes to the severity of intestinal inflammation. Gastroenterology. 2011;141:588–598.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Duffy LC, Zielezny MA, Riepenhoff-Talty M, et al. Vasoactive intestinal peptide as a laboratory supplement to clinical activity index in inflammatory bowel disease. Dig Dis Sci. 1989;34:1528–1535.

    Article  CAS  PubMed  Google Scholar 

  23. Magnusson KE, Stjernström I. Mucosal barrier mechanisms. Interplay between secretory IgA (SIgA), IgG and mucins on the surface properties and association of salmonellae with intestine and granulocytes. Immunology. 1982;45:239–248.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Suzuki K, Maruya M, Kawamoto S, Fagarasan S. Roles of B-1 and B-2 cells in innate and acquired IgA-mediated immunity. Immunol Rev. 2010;237:180–190.

    Article  CAS  PubMed  Google Scholar 

  25. Stanisz AM, Befus D, Bienenstock J. Differential effects of vasoactive intestinal peptide, substance P, and somatostatin on immunoglobulin synthesis and proliferations by lymphocytes from Peyer’s patches, mesenteric lymph nodes, and spleen. J Immunol. 1986;136:152–156.

    CAS  PubMed  Google Scholar 

  26. Pascual DW, Beagley KW, Kiyono H, McGhee JR. Substance P promotes Peyer’s patch and splenic B cell differentiation. Adv Exp Med Biol. 1995;371:55–59.

    Article  Google Scholar 

  27. Pascual DW, Xu-Amano JC, Kiyono H, McGhee JR, Bost KL. Substance P acts directly upon cloned B lymphoma cells to enhance IgA and IgM production. J Immunol. 1991;146:2130–2136.

    CAS  PubMed  Google Scholar 

  28. Fujieda S, Waschek JA, Zhang K, Saxon A. Vasoactive intestinal peptide induces S(alpha)/S(mu) switch circular DNA in human B cells. J Clin Investig. 1996;98:1527–1532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ishioka C, Yoshida A, Kimata H, Mikawa H. Vasoactive intestinal peptide stimulates immunoglobulin production and growth of human B cells. Clin Exp Immunol. 1992;87:504–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hinkle KM, Yue M, Behrouz B, et al. LRRK2 knockout mice have an intact dopaminergic system but display alterations in exploratory and motor co-ordination behaviors. Mol Neurodegener. 2012;7:25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kawashima R, Kawamura YI, Kato R, Mizutani N, Toyama-Sorimachi N, Dohi T. IL-13 receptor alpha2 promotes epithelial cell regeneration from radiation-induced small intestinal injury in mice. Gastroenterology. 2006;131:6130–6141.

    Article  Google Scholar 

  32. Zhang Q, Pan Y, Yan R, et al. Commensal bacteria direct selective cargo sorting to promote symbiosis. Nat Immunol. 2015;16:918–926.

    Article  CAS  PubMed  Google Scholar 

  33. Davies P, Hinkle KM, Sukar NN, et al. Comprehensive characterization and optimization of anti-LRRK2 (leucine-rich repeat kinase 2) monoclonal antibodies. Biochem J. 2013;453:101–113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. West AB, Cowell RM, Daher JP, et al. Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents. J Comp Neurol. 2014;522:2465–2480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Biskup S, Moore DJ, Celsi F, et al. Localization of LRRK2 to membranous and vesicular structures in mammalian brain. Ann Neurol. 2006;60:557–569.

    Article  CAS  PubMed  Google Scholar 

  36. Reinhardt P, Schmid B, Burbulla LF, et al. Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression. Cell Stem Cell. 2013;12:354–367.

    Article  CAS  PubMed  Google Scholar 

  37. Häbig K, Walter M, Poths S, Riess O, Bonin M. RNA interference of LRRK2-microarray expression analysis of a Parkinson’s disease key player. Neurogenetics. 2008;9:83–94.

    Article  PubMed  Google Scholar 

  38. Sepulveda B, Mesias R, Li X, Yue Z, Benson DL. Short- and long-term effects of LRRK2 on axon and dendrite growth. PLoS ONE. 2013;8:e61986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kawakami F, Yabata T, Ohta E, et al. LRRK2 phosphorylates tubulin-associated tau but not the free molecule: LRRK2-mediated regulation of the tau-tubulin association and neurite outgrowth. PLoS ONE. 2012;7:e30834.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chandrasekharan B, Nezami BG, Srinivasan S. Emerging neuropeptide targets in inflammation: NPY and VIP. Am J Physiol Gastrointest Liver Physiol. 2013;304:949–957.

    Article  Google Scholar 

  41. Michalski CW, Autschbach F, Selvaggi F, et al. Increase in substance P precursor mRNA in noninflamed small-bowel sections in patients with Crohn’s disease. Am J Surg. 2007;193:476–481.

    Article  CAS  PubMed  Google Scholar 

  42. Del Valle-Pinero AY, Sherwin LB, Anderson EM, Caudle RM, Henderson WA. Altered vasoactive intestinal peptides expression in irritable bowel syndrome patients and rats with trinitrobenzene sulfonic acid-induced colitis. World J Gastroenterol. 2015;21:155–163.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Winston JH, Li Q, Sarna SK. Paradoxical regulation of ChAT and nNOS expression in animal models of Crohn’s colitis and ulcerative colitis. Am J Physiol Gastrointest Liver Physiol. 2013;305:295–302.

    Article  Google Scholar 

  44. Mora JR, von Andrian UH. Differentiation and homing of IgA-secreting cells. Mucosal Immunol. 2008;1:96–109.

    Article  CAS  PubMed  Google Scholar 

  45. Macpherson AJ, McCoy KD, Johansen FE, Brandtzaeg P. The immune geography of IgA induction and function. Mucosal Immunol. 2008;1:11–22.

    Article  CAS  PubMed  Google Scholar 

  46. Massacand JC, Kaiser P, Ernst B, et al. Intestinal bacteria condition dendritic cells to promote IgA production. PLoS ONE. 2008;3:e2588.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Kang SH, Jin BR, Kim HJ, et al. Lactoferrin combined with retinoic acid stimulates B1 Cells to express IgA isotype and gut-homing molecules. Immune Netw. 2015;15:37–43.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kubo M, Nagashima R, Ohta E, et al. Leucine-rich repeat kinase 2 is a regulator of B cell function, affecting homeostasis, BCR signaling, IgA production, and TI antigen responses. J Neuroimmunol. 2016;292:1–8.

    Article  CAS  PubMed  Google Scholar 

  49. Kaakoush NO. Insight into the role of Erysipelotrichaceae in the human host. Front Cell Infect Microbiol. 2015;5:84.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This study was funded by Kitasato University Research Grant for Young Researchers.

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Authors and Affiliations

  1. Department of Biochemistry, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan

    Tatsunori Maekawa, Hitomi Shimayama, Hiromichi Tsushima, Fumitaka Kawakami, Rei Kawashima & Takafumi Ichikawa

  2. Division of Clinical Immunology, Graduate School of Medical Sciences, Kitasato University, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0373, Japan

    Makoto Kubo

Authors
  1. Tatsunori Maekawa
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  2. Hitomi Shimayama
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  4. Fumitaka Kawakami
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Correspondence to Takafumi Ichikawa.

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Maekawa, T., Shimayama, H., Tsushima, H. et al. LRRK2: An Emerging New Molecule in the Enteric Neuronal System That Quantitatively Regulates Neuronal Peptides and IgA in the Gut. Dig Dis Sci 62, 903–912 (2017). https://doi.org/10.1007/s10620-017-4476-3

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