Leucine-Rich Repeat Kinase 2 Controls the Ca2+/Nuclear Factor of Activated T Cells/IL-2 Pathway during Aspergillus Non-Canonical Autophagy in Dendritic Cells

Alicia Yoke Wei Wong; Vasilis Oikonomou; Giuseppe Paolicelli; Antonella De Luca; Marilena Pariano; Jan Fric; Hock Soon Tay; Paola Ricciardi-Castagnoli; Teresa Zelante

doi:10.3389/fimmu.2018.00210

Leucine-Rich Repeat Kinase 2 Controls the Ca²⁺/Nuclear Factor of Activated T Cells/IL-2 Pathway during Aspergillus Non-Canonical Autophagy in Dendritic Cells

Front Immunol. 2018 Feb 8:9:210. doi: 10.3389/fimmu.2018.00210. eCollection 2018.

Authors

Alicia Yoke Wei Wong^{1

2}, Vasilis Oikonomou³, Giuseppe Paolicelli³, Antonella De Luca³, Marilena Pariano³, Jan Fric^{1

4}, Hock Soon Tay¹, Paola Ricciardi-Castagnoli^{1

5}, Teresa Zelante^{1

3}

Affiliations

¹ Singapore Immunology Network, Agency for Science, Technology and Research, Singapore, Singapore.
² National University of Singapore Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore.
³ Department of Experimental Medicine, University of Perugia, Perugia, Italy.
⁴ Center for Translational Medicine (CTM), International Clinical Research Center (ICRC), St. Anne's University Hospital Brno, Brno, Czechia.
⁵ Toscana Life Sciences Foundation, Siena, Italy.

Abstract

The Parkinson's disease-associated protein, Leucine-rich repeat kinase 2 (LRRK2), a known negative regulator of nuclear factor of activated T cells (NFAT), is expressed in myeloid cells such as macrophages and dendritic cells (DCs) and is involved in the host immune response against pathogens. Since, the Ca²⁺/NFAT/IL-2 axis has been previously found to regulate DC response to the fungus Aspergillus, we have investigated the role played by the kinase LRRK2 during fungal infection. Mechanistically, we found that in the early stages of the non-canonical autophagic response of DCs to the germinated spores of Aspergillus, LRRK2 undergoes progressive degradation and regulates NFAT translocation from the cytoplasm to the nucleus. Our results shed new light on the complexity of the Ca²⁺/NFAT/IL-2 pathway, where LRRK2 plays a role in controlling the immune response of DCs to Aspergillus.

Keywords: Aspergillus; NRON; autophagy; dendritic cell; leucine-rich repeat kinase 2; nuclear factor of activated T cells.

Publication types

Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

Animals
Aspergillosis / immunology*
Aspergillosis / microbiology
Aspergillus / immunology*
Autophagy / immunology*
Calcium / metabolism
Cations, Divalent / metabolism
Cells, Cultured
Dendritic Cells / immunology*
Dendritic Cells / ultrastructure
Disease Models, Animal
Gene Knockdown Techniques
Host-Parasite Interactions / immunology
Humans
Interleukin-2 / metabolism
Intravital Microscopy
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / immunology*
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism
Mice
Mice, Inbred C57BL
Microscopy, Electron, Transmission
NFATC Transcription Factors / metabolism
Proteolysis
RNA, Long Noncoding / genetics
RNA, Long Noncoding / immunology
RNA, Long Noncoding / metabolism
RNA, Small Interfering / metabolism
Signal Transduction / immunology*
Spores, Fungal / immunology
Time-Lapse Imaging

Substances

Cations, Divalent
Interleukin-2
NFATC Transcription Factors
NRON long non-coding RNA, mouse
RNA, Long Noncoding
RNA, Small Interfering
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Lrrk2 protein, mouse
Calcium