Leucine-Rich Repeat Kinase 2 Controls Inflammatory Cytokines Production through NF-κB Phosphorylation and Antigen Presentation in Bone Marrow-Derived Dendritic Cells

• Published in: International journal of molecular sciences 2020-03, Vol.21 (5), p.1890
• Main Authors: Kubo, Makoto, Nagashima, Ryuichi, Kurihara, Mitsue, Kawakami, Fumitaka, Maekawa, Tatsunori, Eshima, Koji, Ohta, Etsuro, Kato, Hirotomo, Obata, Fumiya
• Format: Article
• Language: English
• Subjects: Animals; Antigen Presentation; Autophagy; Bone marrow; Bone Marrow Cells - cytology; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; Cell culture; Cell Differentiation - drug effects; Cell Line; Cell Proliferation; Colony-stimulating factor; Cytokines; Cytokines - metabolism; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - drug effects; Dendritic Cells - metabolism; Differentiation; Extracellular signal-regulated kinase; Flow cytometry; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Immune system; Immunization; Infections; Inflammation; Inflammatory bowel disease; Kinases; Leprosy; Leucine; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - metabolism; Leukocytes (granulocytic); Lipopolysaccharides; Lipopolysaccharides - adverse effects; LRRK2 protein; Lymphocytes T; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B - metabolism; NF-κB protein; Parkinson's disease; Pathogens; Phosphorylation; Phosphorylation - drug effects; Rodents; Signal transduction; Stimulation; Studies; Transcription factors; Tumor necrosis factor-TNF
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21051890

Leucine-rich repeat kinase 2 (LRRK2) is the causal molecule of familial Parkinson's disease. Although the characteristics of LRRK2 have gradually been revealed, its true physiological functions remain unknown. LRRK2 is highly expressed in immune cells such as B2 cells and macrophages, suggesting that it plays important roles in the immune system. In the present study, we investigate the roles of LRRK2 in the immune functions of dendritic cells (DCs). Bone marrow-derived DCs from both C57BL/6 wild-type (WT) and LRRK2 knockout (KO) mice were induced by culture with granulocyte/macrophage-colony stimulating factor (GM/CSF) in vitro. We observed the differentiation of DCs, the phosphorylation of the transcriptional factors NF-κB, Erk1/2, and p-38 after lipopolysaccharide (LPS) stimulation and antigen-presenting ability by flow cytometry. We also analyzed the production of inflammatory cytokines by ELISA. During the observation period, there was no difference in DC differentiation between WT and LRRK2-KO mice. After LPS stimulation, phosphorylation of NF-κB was significantly increased in DCs from the KO mice. Large amounts of inflammatory cytokines were produced by DCs from KO mice after both stimulation with LPS and infection with . CD4 T-cells isolated from antigen-immunized mice proliferated to a significantly greater degree upon coculture with antigen-stimulated DCs from KO mice than upon coculture with DCs from WT mice. These results suggest that LRRK2 may play important roles in signal transduction and antigen presentation by DCs.