PARK7/DJ-1 deficiency impairs microglial activation in response to LPS-induced inflammation

被引:5
作者
Mogensen, Frida Lind-Holm [1 ,2 ]
Sousa, Carole [1 ,3 ]
Ameli, Corrado [4 ]
Badanjak, Katja [5 ]
Pereira, Sandro L. [5 ]
Muller, Arnaud [6 ,7 ]
Kaoma, Tony [6 ]
Coowar, Djalil [8 ]
Scafidi, Andrea [1 ,2 ]
Poovathingal, Suresh K. [4 ,9 ]
Tziortziou, Maria [5 ]
Antony, Paul M. A. [10 ]
Nicot, Nathalie [7 ]
Ginolhac, Aurelien [11 ]
Weisenhorn, Daniela M. Vogt [12 ,13 ]
Wurst, Wolfgang [12 ,13 ,14 ,15 ,16 ]
Poli, Aurelie [1 ]
Nazarov, Petr V. [6 ,17 ]
Skupin, Alexander [4 ,18 ,19 ]
Gruenewald, Anne [5 ,20 ]
Michelucci, Alessandro [1 ]
机构
[1] Luxembourg Inst Hlth, Dept Canc Res, Neuroimmunol Grp, 6A Rue Nicolas Ernest Barble, L-1210 Luxembourg, Luxembourg
[2] Univ Luxembourg, Fac Sci Technol & Med, L-4365 Esch Sur Alzette, Luxembourg
[3] Int Iberian Nanotechnol Lab, P-4715330 Braga, Portugal
[4] Univ Luxembourg, Luxembourg Ctr Syst Biomed, Integrat Cell Signalling Grp, L-4362 Esch Sur Alzette, Luxembourg
[5] Univ Luxembourg, Luxembourg Ctr Syst Biomed, Mol & Funct Neurobiol Grp, L-4362 Esch Sur Alzette, Luxembourg
[6] Luxembourg Inst Hlth, Dept Med Informat, Bioinformat Platform, L-1445 Strassen, Luxembourg
[7] Luxembourg Inst Hlth & Lab Natl Sante, LuxGen Genome Ctr, L-3555 Dudelange, Luxembourg
[8] Univ Luxembourg, Luxembourg Ctr Syst Biomed, Rodent Platform, L-4362 Esch Sur Alzette, Luxembourg
[9] Katholieke Univ Leuven, Single Cell Analyt & Microfluid Core, Vlaams Inst Biotechnol, B-3000 Louvain, Belgium
[10] Univ Luxembourg, Luxembourg Ctr Syst Biomed, Bioimaging Platform, L-4362 Esch Sur Alzette, Luxembourg
[11] Univ Luxembourg, Fac Sci Technol & Med, Dept Life Sci & Med, L-4365 Esch Sur Alzette, Luxembourg
[12] German Res Ctr Environm Hlth, Inst Dev Genet, Helmholtz Zentrum Munchen, D-85764 Neuherberg, Germany
[13] Tech Univ Munchen Weihenstephan, D-85354 Freising Weihenstephan, Germany
[14] German Ctr Neurodegenerat Dis DZNE, D-81377 Munich, Germany
[15] Munich Cluster Syst Neurol SyNergy, D-81377 Munich, Germany
[16] Deutsch Zentrum Psych Gesundheit DZPG, D-80336 Munich, Germany
[17] Luxembourg Inst Hlth, Dept Canc Res, Multi Data Sci Grp, L-1445 Strassen, Luxembourg
[18] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA
[19] Univ Luxembourg, Dept Phys & Mat Sci, Integrat Biophys, L-1511 Luxembourg, Luxembourg
[20] Univ Lubeck, Inst Neurogenet, D-23538 Lubeck, Germany
关键词
PARK7/DJ-1; Lipopolysaccharide; Microglia; Neuroinflammation; Parkinson's disease; Microglia morphology; PARKINSONS-DISEASE; DJ-1-DEFICIENT MICE; OXIDIZED DJ-1; PROTEIN; PROFILE; RISK; PET;
D O I
10.1186/s12974-024-03164-x
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
BackgroundSpecific microglia responses are thought to contribute to the development and progression of neurodegenerative diseases, including Parkinson's disease (PD). However, the phenotypic acquisition of microglial cells and their role during the underlying neuroinflammatory processes remain largely elusive. Here, according to the multiple-hit hypothesis, which stipulates that PD etiology is determined by a combination of genetics and various environmental risk factors, we investigate microglial transcriptional programs and morphological adaptations under PARK7/DJ-1 deficiency, a genetic cause of PD, during lipopolysaccharide (LPS)-induced inflammation. MethodsUsing a combination of single-cell RNA-sequencing, bulk RNA-sequencing, multicolor flow cytometry and immunofluorescence analyses, we comprehensively compared microglial cell phenotypic characteristics in PARK7/DJ-1 knock-out (KO) with wildtype littermate mice following 6- or 24-h intraperitoneal injection with LPS. For translational perspectives, we conducted corresponding analyses in human PARK7/DJ-1 mutant induced pluripotent stem cell (iPSC)-derived microglia and murine bone marrow-derived macrophages (BMDMs). ResultsBy excluding the contribution of other immune brain resident and peripheral cells, we show that microglia acutely isolated from PARK7/DJ-1 KO mice display a distinct phenotype, specially related to type II interferon and DNA damage response signaling, when compared with wildtype microglia, in response to LPS. We also detected discrete signatures in human PARK7/DJ-1 mutant iPSC-derived microglia and BMDMs from PARK7/DJ-1 KO mice. These specific transcriptional signatures were reflected at the morphological level, with microglia in LPS-treated PARK7/DJ-1 KO mice showing a less amoeboid cell shape compared to wildtype mice, both at 6 and 24 h after acute inflammation, as also observed in BMDMs. ConclusionsTaken together, our results show that, under inflammatory conditions, PARK7/DJ-1 deficiency skews microglia towards a distinct phenotype characterized by downregulation of genes involved in type II interferon signaling and a less prominent amoeboid morphology compared to wildtype microglia. These findings suggest that the underlying oxidative stress associated with the lack of PARK7/DJ-1 affects microglia neuroinflammatory responses, which may play a causative role in PD onset and progression.
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页数:24
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