LRRK2 is Involved in the IFN-gamma Response and Host Response to Pathogens

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2010 Oct 6

PMID 20921534

Citations 222

Authors

Agnes Gardet

Yair Benita

Chun Li

Bruce E Sands

Isabel Ballester

Christine Stevens

Joshua R Korzenik

John D Rioux

Mark J Daly

Ramnik J Xavier

Daniel K Podolsky

Affiliations

Soon will be listed here.

Abstract

LRRK2 was previously identified as a defective gene in Parkinson's disease, and it is also located in a risk region for Crohn's disease. In this study, we aim to determine whether LRRK2 could be involved in immune responses. We show that LRRK2 expression is enriched in human immune cells. LRRK2 is an IFN-γ target gene, and its expression increased in intestinal tissues upon Crohn's disease inflammation. In inflamed intestinal tissues, LRRK2 is detected in the lamina propria macrophages, B-lymphocytes, and CD103-positive dendritic cells. Furthermore, LRRK2 expression enhances NF-κB-dependent transcription, suggesting its role in immune response signaling. Endogenous LRRK2 rapidly translocates near bacterial membranes, and knockdown of LRRK2 interferes with reactive oxygen species production during phagocytosis and bacterial killing. These observations indicate that LRRK2 is an IFN-γ target gene, and it might be involved in signaling pathways relevant to Crohn's disease pathogenesis.

Citing Articles

The interrelationship between intestinal immune cells and enteric α-synuclein in the progression of Parkinson's disease.

Cheng Y, Chiang H Neurol Sci. 2025; .

PMID: 40085320 DOI: 10.1007/s10072-025-08114-w.

Inhibition of LRRK2 Ameliorates Aspergillus fumigatus Keratitis by Regulating STING Signaling Pathways.

Han F, Wang L, Wu J, Shen L, Li Y, Guo H Invest Ophthalmol Vis Sci. 2025; 66(2):13.

PMID: 39908129 PMC: 11804891. DOI: 10.1167/iovs.66.2.13.

Advancements in Immunity and Dementia Research: Highlights from the 2023 AAIC Advancements: Immunity Conference.

Kloske C, Mahinrad S, Barnum C, Batista A, Bradshaw E, Butts B Alzheimers Dement. 2024; 21(1):e14291.

PMID: 39692624 PMC: 11772715. DOI: 10.1002/alz.14291.

LRRK2 is not required for lysozyme expression in Paneth cells.

Tasegian A, Dikovskaya D, Scott M, Chawla A, Pemberton R, Helps T Nat Immunol. 2024; 25(11):2037-2039.

PMID: 39379660 DOI: 10.1038/s41590-024-01972-0.

Infections in the Etiology of Parkinson's Disease and Synucleinopathies: A Renewed Perspective, Mechanistic Insights, and Therapeutic Implications.

Mercado G, Kaeufer C, Richter F, Peelaerts W J Parkinsons Dis. 2024; 14(7):1301-1329.

PMID: 39331109 PMC: 11492057. DOI: 10.3233/JPD-240195.

References

Fais S, Capobianchi M, Pallone F, Di Marco P, Boirivant M, Dianzani F . Spontaneous release of interferon gamma by intestinal lamina propria lymphocytes in Crohn's disease. Kinetics of in vitro response to interferon gamma inducers. Gut. 1991; 32(4):403-7. PMC: 1379080. DOI: 10.1136/gut.32.4.403. View

Fuss I, Neurath M, Boirivant M, Klein J, de La Motte C, Strong S . Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol. 1996; 157(3):1261-70. View

Maekawa T, Kubo M, Yokoyama I, Ohta E, Obata F . Age-dependent and cell-population-restricted LRRK2 expression in normal mouse spleen. Biochem Biophys Res Commun. 2010; 392(3):431-5. DOI: 10.1016/j.bbrc.2010.01.041. View

Luzon-Toro B, de la Torre E, Delgado A, Perez-Tur J, Hilfiker S . Mechanistic insight into the dominant mode of the Parkinson's disease-associated G2019S LRRK2 mutation. Hum Mol Genet. 2007; 16(17):2031-9. DOI: 10.1093/hmg/ddm151. View

Zhang F, Huang W, Chen S, Sun L, Liu H, Li Y . Genomewide association study of leprosy. N Engl J Med. 2009; 361(27):2609-18. DOI: 10.1056/NEJMoa0903753. View

Westerlund M, Belin A, Anvret A, Bickford P, Olson L, Galter D . Developmental regulation of leucine-rich repeat kinase 1 and 2 expression in the brain and other rodent and human organs: Implications for Parkinson's disease. Neuroscience. 2008; 152(2):429-36. DOI: 10.1016/j.neuroscience.2007.10.062. View

West A, Moore D, Choi C, Andrabi S, Li X, Dikeman D . Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum Mol Genet. 2007; 16(2):223-32. DOI: 10.1093/hmg/ddl471. View

West A, Moore D, Biskup S, Bugayenko A, Smith W, Ross C . Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A. 2005; 102(46):16842-7. PMC: 1283829. DOI: 10.1073/pnas.0507360102. View

Wu Z, Irizarry R . Preprocessing of oligonucleotide array data. Nat Biotechnol. 2004; 22(6):656-8. DOI: 10.1038/nbt0604-656b. View

10.

Huang S, Hendriks W, Althage A, Hemmi S, Bluethmann H, Kamijo R . Immune response in mice that lack the interferon-gamma receptor. Science. 1993; 259(5102):1742-5. DOI: 10.1126/science.8456301. View

11.

Xavier R, Rioux J . Genome-wide association studies: a new window into immune-mediated diseases. Nat Rev Immunol. 2008; 8(8):631-43. PMC: 2750781. DOI: 10.1038/nri2361. View

12.

Jorgensen N, Peng Y, Ho C, Rideout H, Petrey D, Liu P . The WD40 domain is required for LRRK2 neurotoxicity. PLoS One. 2009; 4(12):e8463. PMC: 2794542. DOI: 10.1371/journal.pone.0008463. View

13.

Kruger R . LRRK2 in Parkinson's disease - drawing the curtain of penetrance: a commentary. BMC Med. 2008; 6:33. PMC: 2607298. DOI: 10.1186/1741-7015-6-33. View

14.

Uhlig H, McKenzie B, Hue S, Thompson C, Joyce-Shaikh B, Stepankova R . Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology. Immunity. 2006; 25(2):309-18. DOI: 10.1016/j.immuni.2006.05.017. View

15.

Breese E, Braegger C, Corrigan C, Walker-Smith J, MacDonald T . Interleukin-2- and interferon-gamma-secreting T cells in normal and diseased human intestinal mucosa. Immunology. 1993; 78(1):127-31. PMC: 1421783. View

16.

Chen H, Jacobs E, Schwarzschild M, McCullough M, Calle E, Thun M . Nonsteroidal antiinflammatory drug use and the risk for Parkinson's disease. Ann Neurol. 2005; 58(6):963-7. DOI: 10.1002/ana.20682. View

17.

Whitton P . Inflammation as a causative factor in the aetiology of Parkinson's disease. Br J Pharmacol. 2007; 150(8):963-76. PMC: 2013918. DOI: 10.1038/sj.bjp.0707167. View

18.

MacDonald T, Hutchings P, Choy M, Murch S, Cooke A . Tumour necrosis factor-alpha and interferon-gamma production measured at the single cell level in normal and inflamed human intestine. Clin Exp Immunol. 1990; 81(2):301-5. PMC: 1535044. DOI: 10.1111/j.1365-2249.1990.tb03334.x. View

19.

Niessner M, Volk B . Altered Th1/Th2 cytokine profiles in the intestinal mucosa of patients with inflammatory bowel disease as assessed by quantitative reversed transcribed polymerase chain reaction (RT-PCR). Clin Exp Immunol. 1995; 101(3):428-35. PMC: 1553229. DOI: 10.1111/j.1365-2249.1995.tb03130.x. View

20.

Paisan-Ruiz C, Jain S, Evans E, Gilks W, Simon J, van der Brug M . Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron. 2004; 44(4):595-600. DOI: 10.1016/j.neuron.2004.10.023. View