α-Synuclein fibrils recruit peripheral immune cells in the rat brain prior to neurodegeneration

Abstract

Genetic variation in a major histocompatibility complex II (MHCII)-encoding gene (HLA-DR) increases risk for Parkinson disease (PD), and the accumulation of MHCII-expressing immune cells in the brain correlates with α-synuclein inclusions. However, the timing of MHCII-cell recruitment with respect to ongoing neurodegeneration, and the types of cells that express MHCII in the PD brain, has been difficult to understand. Recent studies show that the injection of short α-synuclein fibrils into the rat substantia nigra pars compacta (SNpc) induces progressive inclusion formation in SNpc neurons that eventually spread to spiny projection neurons in the striatum. Herein, we find that α-synuclein fibrils rapidly provoke a persistent MHCII response in the brain. In contrast, equivalent amounts of monomeric α-synuclein fail to induce MHCII or persistent microglial activation, consistent with our results in primary microglia. Flow cytometry and immunohistochemical analyses reveal that MHCII-expressing cells are composed of both resident microglia as well as cells from the periphery that include monocytes, macrophages, and lymphocytes. Over time, α-Synuclein fibril exposures in the SNpc causes both axon loss as well as monocyte recruitment in the striatum. While these monocytes in the striatum initially lack MHCII expression, α-synuclein inclusions later form in nearby spiny projection neurons and MHCII expression becomes robust. In summary, in the rat α-synuclein fibril model, peripheral immune cell recruitment occurs prior to neurodegeneration and microglia, monocytes and macrophages all contribute to MHCII expression.Electronic supplementary materialThe online version of this article (10.1186/s40478-017-0494-9) contains supplementary material, which is available to authorized users.

Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson’s disease

“…Our data are in line with other studies reporting peripheral inflammation in PD, including changes in patients' blood immune cells [60][61][62] . Of note, the reduction of peripheral monocytes in Syn rats might explain the increased Iba1 + cell numbers in SNpc, striatum and hippocampus, given that both resident microglia and infiltrated monocyte-derived macrophages can express Iba1, in line with recent evidence of monocyte, T-or B-cell infiltration in α-syn based models [63][64][65][66] . Nonetheless, we cannot exclude other possible explanations for blood monocyte reduction in Syn rats, including cell death following inflammatory activation or re-mobilization from primary/secondary lymphoid organs, including bone marrow and spleen, where they are recruited for clearance.…”

Immune system responses in Parkinson's disease: Early and dynamic

“…It is suggested that during neurodegeneration peripheral monocytes/macrophages (as mentioned, different myeloid cells than microglia) infiltrate the CNS. Accordingly, proteins that are highly expressed in monocytes/macrophages but not in brain‐resident microglia, such as the scavenger receptor CD163 (Polfliet, Fabriek, Daniels, Dijkstra, & van den Berg, ); or the chemokine receptor CCR2 (Mizutani et al., ), are present in cells that infiltrate the brain of animal models of PD‐like degeneration (Harms et al., , ; Tentillier et al., ) and in PD and Alzheimer's patients’ brains postmortem (Pey, Pearce, Kalaitzakis, Griffin, & Gentleman, ). Furthermore, analyses of blood cells in patients revealed changes in the immune compartment during active disease.…”

“…Monocytes in CSF from PD patients display higher HLA‐DR (MHCII) expression compared to those in blood (Fiszer, Mix, Fredrikson, Kostulas, & Link, ) and interestingly, monocytes infiltrating the brain in a rodent viral‐vector‐a‐syn PD model also express high levels of MHCII (Harms et al., ). Parkinson's disease patient monocytes also display elevated TLR2 and TLR4 expression (Drouin‐Ouellet et al., ), two receptors reported to interact with a‐syn (Fellner et al., ; Kim et al., ).…”

Pathologic α-Synuclein Species Activate LRRK2 in Pro-Inflammatory Monocyte and Macrophage Responses

“…Emerging evidence suggests immune cell activation follows intracranial injections of -synuclein fibrils in rodent models, with our past results in rats suggesting recruitment of T-cells and mixed myeloid cells (e.g., CD45 hi /CD11b+ cells) after -synuclein fibril injections (Harms et al, 2017a). In cortico-striatal brain lysates from WT (nTg) C57BL/6J mice one-month after intrastriatal injection of 20 nM rod--synuclein fibrils, we observed a marked increase in Rab10 phosphorylation with reduced LRRK2 protein ( Figure 1J-L).…”

“…Although many different abnormal conformations and post-translational modifications of -synuclein have been associated with neurotoxicity and PD, in the last ten years, recombinant -synuclein short-fibrils have gained particular notoriety for their ability to template new fibril formation from endogenous -synuclein expression in neurons (Luk et al, 2012;Volpicelli-Daley et al, 2011). Our results in rat brain demonstrate that these fibrils are not inert with respect to neuroinflammation, but demonstrate that intracranial injections of fibrils (but not monomeric protein) result in significant recruitment of CD45 hi /CD11b+ cells and T-cells to the rat brain (Harms et al, 2017a). Experiments ex vivo in human monocytes demonstrate that -synuclein rod-fibrils specifically result in pro-inflammatory responses at very low concentrations that includes the production and release of IL-6 (Grozdanov et al, 2019).…”