Anti-Inflammatory Modulation of Microglia via CD163-Targeted Glucocorticoids Protects Dopaminergic Neurons in the 6-OHDA Parkinson's Disease Model.
Increasing evidence supports a decisive role for inflammation in the neurodegenerative process of Parkinson's disease (PD). The immune response in PD seems to involve, not only microglia, but also other immune cells infiltrated into the brain. Indeed, we observed here the infiltration of macrophages, specifically CD163+ macrophages, into the area of neurodegeneration in the 6-hydroxydopamine (6-OHDA) PD model. Therefore, we investigated the therapeutic potential of the infiltrated CD163+ macrophages to modulate local microglia in the brain to achieve neuroprotection. To do so, we designed liposomes targeted for the CD163 receptor to deliver dexamethasone (Dexa) into the CD163+ macrophages in the 6-OHDA PD model. Our data show that a fraction of the CD163-targeted liposomes were carried into the brain after peripheral intravenous injection. The 6-OHDA-lesioned rats that received repeated intravenous CD163-targeted liposomes with Dexa for 3 weeks exhibited better motor performance than the control groups and had minimal glucocorticoid-driven side effects. Furthermore, these animals showed better survival of dopaminergic neurons in substantia nigra and an increased number of microglia expressing major histocompatibility complex II. Therefore, rats receiving CD163-targeted liposomes with Dexa were partially protected against 6-OHDA-induced dopaminergic neurodegeneration, which correlated with a distinctive microglia response. Altogether, our data support the use of macrophages for the modulation of brain neurodegeneration and specifically highlight the potential of CD163-targeted liposomes as a therapeutic tool in PD.



The immune response now evident in the progression of Parkinson's disease comprises both local microglia and other immune cells. We provide evidence that CD163+ macrophages can be a target to modulate brain immune response to achieve neuroprotection in the 6-hydroxydopamine model. To do so, we targeted the CD163+ population, which to a low but significant extent infiltrated in the neurodegenerating area of the brain. Specially designed liposomes targeted for the CD163 receptor were loaded with glucocorticoids and injected peripherally to modify the infiltrated CD163 cells toward an anti-inflammatory profile. This modification of the CD163 population resulted in a distinctive microglial response that correlated with decreased dopaminergic cell death and better motor performance.
CNS Disease Modeling Group, NEURODIN, Department of Biomedicine, and.
Noemie
0000-0002-0161-662X
N
Tentillier
Department of Biomedicine, and.
Anders
0000-0002-6757-2068
A
Etzerodt
CNS Disease Modeling Group, NEURODIN, Department of Biomedicine, and.
Mads N
0000-0001-6471-3374
MN
Olesen
CNS Disease Modeling Group, NEURODIN, Department of Biomedicine, and.
F Sila
FS
Rizalar
Department of Clinical Medicine, PET Center, Aarhus University Hospital, DK-8000 Aarhus C, Denmark, and.
Jan
0000-0003-2617-7042
J
Jacobsen
Department of Clinical Medicine, PET Center, Aarhus University Hospital, DK-8000 Aarhus C, Denmark, and.
Dirk
0000-0001-6339-0518
D
Bender
Department of Biomedicine, and Department of Cancer and Inflammation Research, Syddansk University, DK-5000 Odense, Denmark.
Søren K
0000-0003-3862-2107
SK
Moestrup
CNS Disease Modeling Group, NEURODIN, Department of Biomedicine, and mrr@biomed.au.dk.
Marina
0000-0003-0970-578X
M
Romero-Ramos
D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects*; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism*; D006854:Hydrocortisone / Q000097:blood; D008081:Liposomes / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D017628:Microglia / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D000098902:CD163 Antigen
D018663:Adrenergic Agents; D000893:Anti-Inflammatory Agents; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D005938:Glucocorticoids; D008081:Liposomes; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D006854:Hydrocortisone
CD163; Parkinson's disease; dexamethasone; dopamine; macrophages; microglia