Jae-Kyung Lee

The NLRP3 inflammasome is a central mediator of metabolic inflammation, yet the upstream mechanisms remain poorly defined. We identified RGS10 as a critical regulator of NLRP3-driven immunometabolic responses. In macrophages, loss of RGS10 enhanced calcium-dependent NLRP3 inflammasome activity during both priming and activation. In high-fat diet-fed male mice, Nlrp3 deletion improved glucose tolerance, adipose remodeling, and hepatic and hypothalamic pathology, whereas Rgs10 deletion induced the opposite phenotype. These benefits required RGS10: in Nlrp3 ^-/-/ Rgs10 ^-/- (dKO) males, the improvements in glucose tolerance, adipose remodeling, and hypothalamic microgliosis were abolished. This requirement was selective; RGS10 acted dominantly to restrain myeloid and hepatic inflammation independent of NLRP3, and the interaction was sex-dependent. Finally, RGS10 declined in aged and Parkinson’s disease human microglia, and aged Rgs10 ^-/- mice developed glucose intolerance. Together, these findings establish RGS10 as a dominant, sex-dependent upstream regulator of NLPR3-driven inflammation, suggesting that age- or inflammation-associated RGS10 loss may limit the efficacy of NLRP3-targeted therapies.

Background: Natural killer (NK) cells are key effector lymphoid cells involved in both innate and adaptive immunity and are capable of clearing abnormally aggregated α-synuclein (αSyn). In preclinical Parkinson’s disease (PD) models, NK cell depletion worsens motor deficits and increases insoluble αSyn accumulation, suggesting a neuroprotective role. However, the therapeutic potential of NK cell transfer in modulating αSyn pathology and neurodegeneration remains unexplored. Methods: To assess the efficacy of NK cell therapy, we administered biweekly systemic injections of untouched NK cells isolated from B6C3H donor mice into 2-month-old presymptomatic homozygous M83 transgenic mice injected with human αSyn preformed fibrils. Neurological function was assessed via clasping behavior and clinical scoring. αSyn pathology and dopaminergic neurodegeneration were evaluated via immunohistochemistry. CyTOF-based immune profiling and multiplex ELISA were performed to characterize central and peripheral immune responses. Results: Adoptive NK cell transfers improved motor function and reduced αSyn pathology in a region- and dose-dependent manner, with significant reductions in phosphorylated-αSyn inclusions and tyrosine hydroxylase-positive neuronal loss in the substantia nigra. NK cell transfer modulated the CNS immune landscape by reducing CD11b ⁺ CD45 ^high and MHCII ⁺ activated microglial, CD4⁺ T cells, and neutrophil infiltration, while promoting CD19 ⁺ B and CD8 ⁺ T cells. Similar immunomodulatory effects were observed in the periphery, including restoration of follicular B cells and reduced neutrophil frequencies. Mechanistically, αSyn exposure downregulated activating NK ligands and upregulated inhibitory receptor ligand mQa1b, along with p21 induction in microglia, suggesting a senescence-associated, immune-evasive phenotype that may contribute to reduced therapeutic efficacy at later disease stages. Conclusions: Our study provides direct evidence of NK cells exerting neuroprotective and immunomodulatory effects in a preclinical model of synucleinopathy. These findings support NK cell transfer as a novel therapeutic strategy for PD and related neurodegenerative disorders.

Microglia play a critical role in maintaining brain homeostasis but become dysregulated in neurodegenerative diseases. Regulator of G-protein Signaling 10 (RGS10), one of the most abundant homeostasis proteins in microglia, decreases with aging and functions as a negative regulator of microglia activation. RGS10-deficient mice exhibit impaired glucose tolerance, and high-fat diet induces insulin resistance in these mice. In this study, we investigated whether RGS10 modulates microglia activation in response to hyperglycemic conditions, complementing our previous findings of its role in inflammatory stimuli. In RGS10 knockdown (KD) BV2 cells, TNF production increased significantly in response to high glucose, particularly under proinflammatory conditions. Additionally, glucose uptake and GLUT1 mRNA levels were significantly elevated in RGS10 KD BV2 cells. These cells produced higher ROS and displayed reduced sensitivity to the antioxidant N-Acetyl Cysteine (NAC) when exposed to high glucose. Notably, both BV2 cells and primary microglia that lack RGS10 exhibited impaired uptake of alpha-synuclein aggregates. These findings suggest that RGS10 acts as a negative regulator of microglia activation not only in response to inflammation but also under hyperglycemic conditions.

Mounting data suggest an important role for the immune system in Parkinson’s disease (PD). Previous evidence of increased natural killer (NK) cell populations in PD suggests a potential role of NK cells in the pathogenesis of the disease. Previous studies have analyzed NK cell populations using aggregation by variable expression of CD56 and CD16. It remains unknown what differences may exist between NK cell subpopulations when stratified using more nuanced classification. Here, we profile NK cell subpopulations and elucidate the expressions of activating, NKG2D, inhibitory, NKG2A, and homing, CX3CR1, receptors on NK cell subpopulations in PD and healthy controls (HC). We analyzed cryopreserved PMBC samples using a 10-color flow cytometry panel to evaluate NK cell subpopulations in 31 individuals with sporadic PD and 27 HC participants. Here we identified significant differences in the CD56^dim NK subset that changes with disease severity in PD. Furthermore, the expressions of NKG2D in all three NK cell subsets were significantly elevated in PD patients compared to HC. Notably, NKG2A expression in the CD56^bright NK subset increased in PD patients with longer disease duration but there were no changes in CX3CR1. In summary, our data suggests that changes in NK cells may be influenced by the clinical severity and duration of PD.

Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by the loss of dopaminergic neurons in the substantia nigra and the abnormal aggregation and accumulation of the alpha-synuclein (α-syn) protein into Lewy bodies. It is established that there is an association between inflammation and PD; however, the time course of the inflammatory process as well as the immune cells involved are still debated. Natural killer (NK) cells are innate lymphocytes with numerous functions including targeting and killing infected or malignant cells, antimicrobial defense, and resolving inflammation. NK cell subsets differ in their effector function capacities which are modulated by activating and inhibitory receptors expressed at the cell surface. Alterations in NK cell numbers and receptor expression have been reported in PD patients. Recently, NK cell numbers and frequency were shown to be altered in the periphery and in the central nervous system in a preclinical mouse model of PD. Moreover, NK cells have recently been shown to internalize and degrade α-syn aggregates and systemic NK cell depletion exacerbated synuclein pathology in a preclinical mouse model of PD, indicating a potential protective role of NK cells. Here, we review the inflammatory process in PD with a particular focus on alterations in NK cell numbers, phenotypes, and functions.

Mounting data suggest an important role of the immune system in Parkinson’s disease (PD). Previous evidence of increased natural killer (NK) cell populations in PD suggests a potential role of NK cells in the pathogenesis of the disease. Previous studies have analyzed NK populations using aggregation by a variable expression of CD56 and CD16. It remains unknown what differences may exist between NK cell subpopulations when stratified using more nuanced classification. Here we profile NK cell subpopulations and elucidate the expressions of activating NKG2D receptor, inhibitory NKG2A receptor, and homing CX3CR1 receptor on NK cell subpopulations in PD and healthy controls (HC). The cryopreserved PBMC samples were analyzed using a 10-color flow cytometry panel to assess NK cell subpopulations on 36 individuals with sporadic PD and 35 HC participants. Among PD cases, we observed that NKG2D frequency and expression level was higher in CD56^bright NK populations in patients with more severe motor symptoms as measured by the UPDRS III. Additionally, NKG2D expression intensity in CD56^bright NK populations was associated with disease duration. NK subpopulations revealed a significant difference in CD56^brightCD16^+/− NK cell subpopulations, with all PD groups showing significantly greater expression of NKG2D on CD56^brightCD16^bright NK cells compared to HC. Overall, we identified changes in NK profiles in PD that change with disease duration and motor symptom severity. Future studies should assess whether these changes in NK populations account for disease progression.

Background: Physiological homeostasis decline, immunosenescence, and increased risk for multiple diseases, including neurodegeneration, are all hallmarks of ageing. Importantly, it is known that the ageing process is sex-biased. For example, there are sex differences in predisposition for multiple age-related diseases, including neurodegenerative and autoimmune diseases. However, sex differences in age-associated immune phenotypes are not clearly understood. Results: Here, we examined the effects of age on immune cell phenotypes in both sexes of C57BL/6J mice with a particular focus on NK cells. We found female-specific spleen weight increases with age and concordant reduction in the number of splenocytes per gram of spleen weight compared to young females. To evaluate sex- and age-associated changes in splenic immune cell composition, we performed flow cytometry analysis. In male mice, we observed an age-associated reduction in the frequencies of monocytes and NK cells; female mice displayed a reduction in B cells, NK cells, and CD8 + T cells and increased frequency of monocytes and neutrophils with age. We then performed a whole blood stimulation assay and multiplex analyses of plasma cytokines and observed age- and sex-specific differences in immune cell reactivity and basal circulating cytokine concentrations. As we have previously illustrated a potential role of NK cells in Parkinson’s disease, an age-related neurodegenerative disease, we further analyzed age-associated changes in NK cell phenotypes and function. There were distinct differences between the sexes in age-associated changes in the expression of NK cell receptors, IFN-γ production, and impairment of α-synuclein endocytosis. Conclusions: This study demonstrates sex- and age-specific alterations in splenic lymphocyte composition, circulating cytokine/chemokine profiles, and NK cell phenotype and effector functions. Our data provide evidence that age-related physiological perturbations differ between the sexes which may help elucidate sex differences in age-related diseases, including neurodegenerative diseases, particularly Parkinson’s disease, where immune dysfunction is implicated in their etiology.

Numerous lines of evidence indicate an association between sustained inflammation and Parkinson’s disease, but whether increased inflammation is a cause or consequence of Parkinson’s disease remains highly contested. Extensive efforts have been made to characterize microglial function in Parkinson’s disease, but the role of peripheral immune cells is less understood. Natural killer cells are innate effector lymphocytes that primarily target and kill malignant cells. Recent scientific discoveries have unveiled numerous novel functions of natural killer cells, such as resolving inflammation, forming immunological memory, and modulating antigen-presenting cell function. Furthermore, natural killer cells are capable of homing to the central nervous system in neurological disorders that exhibit exacerbated inflammation and inhibit hyperactivated microglia. Recently, a study demonstrated that natural killer cells scavenge alpha-synuclein aggregates, the primary component of Lewy bodies, and systemic depletion of natural killer cells results in exacerbated neuropathology in a mouse model of alpha-synucleinopathy, making them a highly relevant cell type in Parkinson’s disease. However, the exact role of natural killer cells in Parkinson’s disease remains elusive. In this review, we introduce the systemic inflammatory process seen in Parkinson’s disease, with a particular focus on the direct and indirect modulatory capacity of natural killer cells in the context of Parkinson’s disease.

The pathological hallmark of synucleinopathies, including Lewy body dementia and Parkinson’s disease (PD), is the presence of Lewy bodies, which are primarily composed of intracellular inclusions of misfolded α-synuclein (α-syn) among other proteins. α-Syn is found in extracellular biological fluids in PD patients and has been implicated in modulating immune responses in the central nervous system (CNS) and the periphery. Natural killer (NK) cells are innate effector lymphocytes that are present in the CNS in homeostatic and pathological conditions. NK cell numbers are increased in the blood of PD patients and their activity is associated with disease severity; however, the role of NK cells in the context of α-synucleinopathies has never been explored. Here, we show that human NK cells can efficiently internalize and degrade α-syn aggregates via the endosomal/lysosomal pathway. We demonstrate that α-syn aggregates attenuate NK cell cytotoxicity in a dose-dependent manner and decrease the release of the proinflammatory cytokine, IFN-γ. To address the role of NK cells in PD pathogenesis, NK cell function was investigated in a preformed fibril α-syn–induced mouse PD model. Our studies demonstrate that in vivo depletion of NK cells in a preclinical mouse PD model resulted in exacerbated motor deficits and increased phosphorylated α-syn deposits. Collectively, our data provide a role of NK cells in modulating synuclein pathology and motor symptoms in a preclinical mouse model of PD, which could be developed into a therapeutic for PD and other synucleinopathies.