Parkinson’s Disease (PD), the second most common neurodegenerative disorder, is primarily characterized by neuroinflammation and progressive degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta, triggered by the pathological aggregation of α-synuclein (α-syn). Leucine-rich repeat kinase 2 (LRRK2) has been implicated in PD pathogenesis, yet its specific role in disease progression and the underlying mechanisms remain inadequately understood. We constructed the α-syn A53T mutant protein and established a neuroinflammatory model using human HMC3 microglial. A conditioned medium transfer system was developed to study microglia-neuron interactions. Expression of LRRK2, NLRP3, Caspase-1, and gasdermin D (GSDMD), key regulators of pyroptosis, was assessed in microglia. We evaluated DA neuronal apoptosis following α-syn A53T stimulation and validated our findings in Prnp-SNCA A53T transgenic PD mice. Our findings demonstrate that α-syn A53T not only elicits a more pronounced neuroinflammatory response but also enhances LRRK2 kinase activity, while LRRK2 inhibition reduced neuroinflammation. Overexpression of LRRK2 led to a marked upregulation of GSDMD and an exacerbation of the inflammatory response, whereas inhibition of the pyroptotic pathway or NLRP3 knockdown effectively mitigated these pathological changes. Using the conditioned medium system, we confirmed that modulation of the LRRK2/NLRP3/pyroptosis axis profoundly influenced DA neuronal survival. In Prnp-SNCA A53T transgenic mice, both pharmacologic inhibition of LRRK2 and genetic silencing of NLRP3 reduced microglial activation and DA neuronal loss in the central nervous system, significantly improving motor deficits and depressive-like behaviors associated with PD. Collectively, our study suggests that LRRK2 may markedly amplify the pyroptotic response by activating the NLRP3/Caspase-1/GSDMD axis, thereby triggering rapid neuroinflammation and influencing the course of Parkinson’s disease. These findings highlight a pivotal role of LRRK2 in orchestrating pyroptosis-related signaling, providing a plausible mechanistic framework to help explain inter-individual heterogeneity in PD progression. Collectively, our results further underscore the translational potential of targeting LRRK2 as a therapeutic strategy for modulating PD progression.

AIM:Parkinson's disease (PD) and progressive supranuclear palsy (PSP) present similar clinical symptoms, but their treatment options and clinical prognosis differ significantly. Therefore, we aimed to discriminate between PD and PSP based on multi-level indices of resting-state functional magnetic resonance imaging (rs-fMRI) via the machine learning approach. MATERIALS AND METHODS:A total of 58 PD and 52 PSP patients were prospectively enrolled in this study. Participants were randomly allocated to a training set and a validation set in a 7:3 ratio. Various rs-fMRI indices were extracted, followed by a comprehensive feature screening for each index. We constructed fifteen distinct combinations of indices and selected four machine learning algorithms for model development. Subsequently, different validation templates were employed to assess the classification results and investigate the relationship between the most significant features and clinical assessment scales. RESULTS:The classification performance of logistic regression (LR) and support vector machine (SVM) models, based on multiple index combinations, was significantly superior to that of other machine learning models and combinations when utilizing automatic anatomical labeling (AAL) templates. This has been verified across different templates. CONCLUSIONS:The utilization of multiple rs-fMRI indices significantly enhances the performance of machine learning models and can effectively achieve the automatic identification of PD and PSP at the individual level.

BackgroundWhile the "swallow tail" sign observed in the substantia nigra (SN) on susceptibility map-weighted imaging (SMWI) serves as an effective marker for differentiating patients with Parkinson's disease (PD) from healthy individuals, its visual assessment proves inadequate in differentiating PD from atypical Parkinson syndromes (APS).PurposeTo employ radiomic features extracted from multi-echo SMWI of the SN to distinguish between PD and APS.Material and MethodsSMWI data were acquired from 63 PD patients, 38 APS patients, and 89 healthy controls. The participants were randomly assigned to either training or test groups in a 7:3 proportion. Utilizing the PyRadiomics software, a set of radiomic features were extracted from SN for analysis. Features underwent standardization via the maximum-minimum method, with 166 statistically significant features identified through independent t-tests. To minimize the risk of overfitting, the least absolute shrinkage and selection operator (LASSO) algorithm was implemented to identify and select the five most significant features from the radiomic dataset. Five distinct machine-learning classifiers were developed to distinguish between PD, APS, and healthy controls. The SHapley Additive Explanations was employed to gain insights into and visualize the relative importance of each feature within these models.ResultsMorphological, first-order, texture, and wavelet transform features of the SN emerged as the most crucial determinants. The light gradient-boosting machine model demonstrated superior performance in distinguishing between PD, APS, and healthy controls.ConclusionRadiomic features of the SN derived from SMWI show promise in differentiating PD from APS, potentially enhancing diagnostic accuracy in clinical settings.

Parkinson's disease is characterized by synucleinopathy-associated neurodegeneration.Previous studies have shown that glucagon-like peptide-1（GLP-1） has beneficial effects in a mouse model of Parkinson s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.However,the effect of GLP-1 on intrinsic synuclein malfunction remains unclear.In this study,we investigated the effect of Lactococcus lactis MG1363-pMG36e-GLP-1 on parkinsonism in Snca A53T transgenic mice and explo red the underlying mechanisms.Our data showed that Lactococcus lactis MG1363-pMG36e-GLP-1 inhibited dopaminergic neuronal death,reduced pathological aggregation of α-synuclein,and decreased movement disorders in SncaA53T transgenic mice.Furthermore,Lactococcus lactis MG1363-pMG36e-GLP-1 downregulated lipopolysaccharide-related inflammation,reduced cerebral activation of microglia and astrocytes,and promoted cell survival via the GLP-1 recepto r/PI3K/Akt pathway in the substantia nigra.Additionally,Lactococcus lactis MG1363-pMG36e-GLP-1 decreased serum levels of pro-inflammato ry molecules including lipopolysaccharide,lipopolysaccharide binding protein,inte rleukin-1β,and interleukin-6.Gut histopathology and western blotting further revealed that Lactococcus lactis MG1363-pMG36e-GLP-1 increased the expression of gut integrity-related proteins and reduced lipopolysaccharide-related inflammation by reve rsing gut dysbiosis in Snca A53T transgenic mice.Our findings showed that the beneficial effect of Lactococcus lactis MG1363-pMG36e-GLP-1 on parkinsonism traits in Snca A53T transgenic mice is mediated by microglial polarization and the reversal of dysbiosis.Collectively,our findings suggest that Lactococcus lactis MG1363-pMG36e-GLP-1 is a promising therapeutic agent for the treatment of Parkinson s disease.

Introduction: The "swallow tail" sign of the substantia nigra on susceptibility map-weighted imaging can distinguish patients with Parkinson's disease from healthy controls. However, differentiating Parkinson's disease from atypical Parkinson syndromes by visually inspecting the swallow tail sign is difficult. This study aimed to distinguish Parkinson's disease from atypical Parkinson syndromes using the radiomic features of the substantia nigra extracted from multiecho susceptibility map-weighted imaging.Methods: Radiomic features were computed from susceptibility map-weighted imaging images of 63 patients with Parkinson's disease, 38 patients with atypical Parkinson syndromes and 89 healthy controls. A randomized division was conducted on a total of 190 participants, assigning them to training and test groups at a 7:3 ratio. and radiomic features were extracted from the substantia nigra using the PyRadiomics package; 166 features passed the t-test. The maximum-minimum standardization method was used to standardize the data on features that passed the independent sample t-test to eliminate the influence of units and magnitudes between different features and ensure the reliability of the results. The least absolute shrinkage and selection algorithm was used to filter out the five features with the highest values to avoid feature overfitting. Five classification models were constructed to identify patients with Parkinson's disease, atypical Parkinson syndromes, and healthy controls. and the weights of selected features were displayed on the model using the SHapley Additive Explanation method.Results: The morphological, first-order, texture and wavelet transform features of the substantia nigra are the most important features, and the light gradient-boosting machine model showed the best performance in identifying Parkinson's disease, atypical Parkinson syndromes, and healthy controls.Conclusions:The radiomic features of the substantia nigra based on susceptibility map-weighted imaging can distinguish Parkinson's disease from atypical Parkinson syndromes.

Background Sitosterolemia, an autosomal recessive condition, is characterized by impaired metabolism of plant sterols. Clinical symptoms include skin xanthoma, premature atherosclerotic disease, arthritis, and unexplained hematological abnormalities. However, there is a dearth of studies on sitosterolemia-related brain damage. Methods This study focused on the family of two sitosterolemia patients who presented with severe hypercholesterolemia and xanthoma. Radiological examinations, biopsies, whole-exome sequencing (WES), and plant sterol tests were conducted. Results The index patient, a 66-year-old female, initially exhibited weakness in both lower limbs and later developed urinary and fecal incontinence. Neuroimaging showed that the falx of the brain had irregular fusiform thickening. Significant tissue edema was observed around the lesions in the bilateral frontal-parietal lobes. Pathological analysis of the biopsied brain lesion revealed extensive cholesterol crystal deposition and lymphocyte infiltration in the matrix. The index patient who experienced cerebral impairment and her sister both carried two compound heterozygous variants in ATP binding cassette transporter G5 (ABCG5). These included the nonsense variants NM_022436: c.751 C > T (p.Q251X) in exon 6 and NM_022436: c.1336 C > T (p.R446X) in exon 10. A notable increase in plant sterol levels was observed in the younger sister of the index patient. Conclusion This study highlights a previously unreported neurological aspect of sitosterolemia. Imaging and pathology findings suggest that cholesterol crystals may be deposited in connective tissues such as the cerebral falx and pia mater through blood circulation.

OBJECTIVE: To learn the mechanisms between gut microbiome and the autoimmunity benefits on Traditional Chinese Medicine (TCM) in central nervous system (CNS), we investigated the neuro-protection effects and gut mircobiota changes of Heshouwu (Radix Polygoni Multiflori) on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).METHODS: Mice were randomly divided into four groups: EAE mice (control phosphate-buffered saline group), 50 mg & BULL;kg-1 & BULL;d-1 Heshouwu (Radix Polygoni Multiflori)-treated EAE mice, 100 mg & BULL;kg-1 & BULL;d-1 Heshouwu (Radix Polygoni Multiflori)-treated EAE mice, and 200 mg & BULL;kg-1 & BULL;d-1 Heshouwu (Radix Polygoni Multiflori)-treated EAE mice. The spinal cords were stained with hematoxylin and eosin (HE) and luxol fast blue for evaluating inflammatory infiltration and demyelination. The percentages of granulocyte macrophage-colony stimulating factor (GM-CSF)+CD4+, interleukin 17 (IL-17)+CD4+, Foxp3 CD4+, and interferon-& gamma; (IFN-& gamma;)+CD4+ T cells in the inguinal lymph nodes (LNs) and brain were determined by flow cytometry analysis. 16S rRNA gene sequencing was employed to analyze the changes in gut microbiota.RESULTS: We found that Heshouwu (Radix Polygoni Multiflori) alleviated the disease severity and neuropathology of EAE as evaluated by clinical and histopathologyical scores. Heshouwu (Radix Polygoni Multiflori) increased the diversity and abundance of the gut microbiota, and decreased Firmicutes/Bacteroidetes ratio (F/B ratio). Heshouwu (Radix Polygoni Multiflori) also decreased the concentrations of IL-10, and IL-21 and increase the levels of GM-CSF, IL-17A, IL-17F and IL-22 in serum of EAE mice. Moreover, Heshouwu (Radix Polygoni Multiflori) modulated the T cell responses by inhibiting Th17 cells and restoring Treg cells in the small intestine lymphoid tissues and inguinal lymph nodes. Microbiota-depleted mice receiving Heshouwu (Radix Polygoni Multiflori)-treated fecal microbiota transplantation had lower disease severity, neuropathology scores and alleviation of Th17/Treg imbalance compared to ad libitum group.CONCLUSIONS: Our findings suggested that the vital neuro-protection role of Heshouwu (Radix Polygoni Multiflori) (TCM) in immunomodulation effects partly by regulations of gut microbiome. & COPY; 2023 JTCM. All rights reserved.

1Department of Radiology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China; 2Neuroimaging Lab, Jiangxi Province Medical Imaging Research Institute, Nanchang, 330006, People’s Republic of China; 3Department of Neurology, Jiangxi Provincial People’s Hospital Affiliated to Nanchang University, Nanchang, 330006, People’s Republic of China; 4Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People’s Republic of China

OBJECTIVE:Clinical symptoms such as major defects in energy metabolism may involve the hypothalamus in amyotrophic lateral sclerosis (ALS) patients. Our recent study discovered that the single-nucleotide polymorphisms (SNPs) of rs2619566, rs79609816 and rs10260404 are associated with sporadic ALS (sALS). Thus, this study aims to investigate the hypothalamic functional reorganization and its association with the above polymorphisms risk alleles in sALS patients of Chinese Han ancestry. METHODS:Forty-four sALS patients (28 males/16 females) and 40 healthy subjects (HS; 28 males/12 females) underwent resting-state functional MRI, genotyping and clinical assessments. A two-sample t test (P < 0.01, GRF correction at P < 0.05) was performed to compare hypothalamic connectivity for group-level analysis in disease diagnosis and genotype, and then the genotype-diagnosis interaction effect was assessed. Finally, Spearman correlation analyses were performed to assess the relationship between the altered functional connectivity and their clinical characteristics. RESULTS:The sALS patients showed a short disease duration (median = 12 months). Regarding the diagnosis effect, the sALS patients showed widespread hypothalamic hyperconnectivity with the left superior temporal gyrus/middle temporal gyrus, right inferior frontal gyrus, and left precuneus/posterior cingulate gyrus. For the genotype effect of SNPs, hyperconnectivity was observed in only the medial hypothalamus when the sALS patients harboring the minor C allele of rs2619566 in contactin-4 (CNTN4), while the sALS patients with the TT allele showed a hyperconnectivity network in the right lateral hypothalamus. This connectivity pattern was not observed in other SNPs. No significant genotype-diagnosis interaction was found. Moreover, altered functional connectivity was not significantly correlated with clinical characteristics (P : 0.11-0.90). CONCLUSION:These results demonstrated widespread hypothalamic hyperconnectivity in sALS. The risk allele C of the CNTN4 gene may therefore influence functional reorganization of the medial hypothalamus. The effects of the CNTN4 rs2619566 polymorphism may exist in the hypothalamic functional connectivity of patients with sALS.

The composition of the gut microbiota, including Akkermansia muciniphila (A. muciniphila), is altered in many neurological diseases and may be involved in the pathophysiological processes of Parkinson’s disease (PD). A. muciniphila, a mucin-degrading bacterium, is a potential next-generation microbe that has anti-inflammatory properties and is responsible for keeping the body healthy. As the role of A. muciniphila in PD has become increasingly apparent, we discuss the potential link between A. muciniphila and various neurological diseases (including PD) in the current review.

Many epidemiological studies have associated coffee consumption with a reduced Parkinson's disease (PD) risk, but the molecular mechanisms remain unclear. In this study, systematic pharmacological and bioinformatics approaches were employed to explore the bioactive components and potential mechanisms mediated by coffee in PD. We identified 12 active compounds in coffee associated with 47 PD-related targets, which might exert synergism because some targets were enriched in multiple signaling pathways and biological processes. The compound-target network and protein-protein interaction network exemplified the multi-component and multitarget effect mediated by coffee in PD. Furthermore, a molecular docking assessment verified the great activity between active compounds identified in coffee and PD-related targets. These results showed that the bioactive components of coffee exerted synergistic effects against PD-associated targets through numerous pathways and provided a new perspective for scientific research exploring the multi-component and multi-target mechanisms mediated by coffee in PD.

Using time-variant of blood oxygenation level dependent (BOLD) signal to investigate the temporal changes in functional connectivity (FC) between key nodes may shed light on the dynamic characteristics of network. Twenty-two relapsing-remitting multiple sclerosis (RRMS) and 22 well-matched healthy control subjects (HCs) participated in this study. Previously validated key nodes of attention network seeds were defined as spherical regions of interests (ROIs); then, we captured the pattern of dFC using sliding window correlation of ROIs in the RRMS and HCs during rest. Furthermore, correlation analysis between altered dFC of paired-ROIs with clinical measures in RRMS were performed. Compared with the HCs, the RRMS showed: a certain specificity transient pattern of FC of attention network at time window levels, including decreased dFC within dorsal attention network [connections of left intraparietal sulcus (LIPS)-right intraparietal sulcus (RIPS), LIPS-right frontal eye field (RFEF) and left frontal eye field (LFEF)-RIPS] and ventral attention network [connection of right ventral frontal cortex (RVFC)-right temporal parietal junction (RTPJ)], increased dFC between dorsal and ventral attention network (connections of LIPS-RTPJ and LIPS-RVFC). Secondary analysis indicated that the dFC coefficients of the connections of LIPS-RIPS (r = -0.467, P = 0.023) and RVFC-RTPJ (r = -0.452, P = 0.043) were significant negative correlated with the total white matter lesion load. In conclusion, we found that the instantaneous configuration pattern of FC in attention network of RRMS are relate to lesions loads.

Background and purpose: The effects of the interactions between the default mode network (DMN) and the dorsal attention network (DAN), which present anticorrelated behaviors, in relapsing-remitting multiple sclerosis (RRMS) are poorly understood. This study used resting-state functional connectivity (FC) and the Granger causality test (GCT) to examine changes in the undirected and effective functional network connectivity (FNC) between the two networks during the remitting phase in RRMS patients. Patients and methods: Thirty-three patients experiencing a clinically diagnosed remitting phase of RRMS and 33 well-matched healthy control subjects participated in this study. First, an independent component (IC) analysis was performed to preprocess the functional magnetic resonance imaging data and select resting-state networks. Then, an FNC analysis and the GCT were combined to examine the temporal correlations between the ICs of the DMN and DAN and to identify correlations with clinical markers. Results: Compared with the healthy subjects, the RRMS patients in the remitting phase showed the following: 1) significantly decreased FC within the DAN in the postcentral gyrus and decreased FC within the DMN in several regions except the parahippocampal gyrus, where increased FC was observed; 2) a relatively stable interaction between the two anticorrelated networks as well as a driving connectivity from the DAN to DMN (IC15); and 3) significantly positive correlations between the connectivity coefficient of the right superior temporal gyrus and the Modified Fatigue Impact Scale score ( ρ = 0.379, p = 0.036). Conclusion: Adaptive mechanisms that maintain stable interactions might occur between the DMN and DAN during the remitting phase in RRMS patients.

Evidences suggest that Cystatin C (Cys C) levels might be a biomarker in amyotrophic lateral sclerosis (ALS) diagnosis, but the conclusion is still in doubts.We conducted a systematic review and meta analysis of Cys C levels in cerebrospinal cord fluid (CSF) and peripheral blood of patients with ALS in order to further confirm whether or not Cys C levels is a biomarker in ALS diagnosis.The English relevant studies without year limitation were systematically searched in PubMed, EMBASE, Web of Science databases.The searched term contained "Amyotrophic Lateral Sclerosis" or "Motor Neuron Diseases" and "Cystatin C" and "Cerebrospinal fluid" or "CSF" or "Biomarker" or "Serum" or "Plasma" or "Blood".Observational studies reporting the associations between Cys C levels and ALS patients were selected to conduct a systematic review and meta analysis.Two reviewers performed the selection of this study independently.The Newcastle-Ottawa Scale assesses the quality and risk of bias of selected studies.Estimates were pooled using a random-effects model.The Cys C levels of CSF or peripheral blood in ALS patients compared with health controls (HCs) and several relevant neurodegenerative diseases (NDDs).Sixteen studies were included in our systematic review, 9 of them were selected to perform the meta analysis.Of these, eight studies measured Cys C levels in CSF and three studies measured it in blood.Cys C levels in CSF were significantly lower in ALS patients than in HCs (Hedge's g = -1.398,95%CI: -2.43 to -0.36; p = 0.008), but there was no statistical difference between ALS patients and several relevant NDDs.No statistically significant difference in the Cys C levels of blood in the comparison between ALS and HCs.The correlation meta analysis presented no significant correlation between Cys C levels in CSF and age or disease duration respectively.Cys C levels significantly decrease in the CSF of ALS patients, but are not a specific biomarker for this disease.Cys C levels in CSF might be an auxiliary diagnostic biomarker of ALS.

More and more studies have demonstrated that bone marrow microenvironment, the fundament of the multiplication and differentiation of hematopoietic stem cells, plays a crucial role in leukemia progression and resistance to treatment. It provides a permissive environment for minimal residual disease and contributes to relapse and multidrug resistance. Mesenchymal stem cells are a kind of important stromal cells in bone marrow niche. In recent researches, MSC have been shown to be one of the major factors modulating the biological features of leukemia cells. The cross-talk between MSC and leukemia cells can take place not only by direct contact, but also by exosome exchange. Exosomes are nano-sized vesicles released by a variety of cells, which contain protein, RNA and mRNA. They are effective tools for transportation between cells, and play an important role in many physiological and pathological processes. Exosome is a new topic in the research of leukemia and microenvironment. The exosome research will help elucidate the mechanism of leukemia, thus providing new ideas for the treatment.

The classical concept that amyotrophic lateral sclerosis (ALS) is a degenerative disorder characterized by the loss of upper and lower motor neurons is agreed. However, more and more studies have suggested the involvement of some extra-motor regions. The aim of this study is to investigate the frequency-related alteration pattern of intrinsic functional connectivity strength (FCS) at the voxel-wise level in the relatively early-stage of ALS on a whole brain scale. In this study, 21 patients with ALS and 21 well-matched healthy control subjects were enrolled to examine the intrinsic FCS in the different frequencies (slow-4: 0.027-0.073 Hz; slow-5: 0.01-0.027 Hz, and typical band: 0.01-0.1 Hz). Compared with the control subjects, the ALS patients showed a significantly decreased FCS in the left prefrontal cortex (PFC) and the bilateral superior frontal gyrus. In the slow-5 band, the patients with ALS showed decreased FCS in the left lingual gyrus, as well as increased FCS in the left postcentral gyrus/paracentral lobule (PoCG/PARC). In the slow-4 band, the ALS patients presented decreased FCS in the left and right ventrolateral PFC. Moreover, the increased FCS in the left PoCG/PARC in the slow-5 band was positively correlated with the ALSFRS-r score (P = 0.015). Our results demonstrated that the FCS changes in ALS were wide spread and frequency dependent. These findings may provide some evidences that ALS patients have the consistent impairment in some extra-motor regions at a relatively early-stage.

Mesenchymal stem cells (MSCs) are ubiquitously present in many tissues. Due to their unique advantages, MSCs have been widely employed in clinical studies. Emerging evidences indicate that MSCs can also migrate to the tumor surrounding stroma and exert complex effects on tumor growth and progression. However, the effect of MSCs on tumor growth is still a matter of debate. Several studies have shown that MSCs could favor tumor growth. On the contrary, other groups have demonstrated that MSCs suppressed tumor progression. Extracellular vesicles have emerged as a new mechanism of cell-to-cell communication in the development of tumor diseases. MSCs-derived extracellular vesicles (MSC-EVs) could mimic the effects of the mesenchymal stem cells from which they originate. Different studies have reported that MSC-EVs may exert various effects on the growth, metastasis, and drug response of different tumor cells by transferring proteins, messenger RNA, and microRNA to recipient cells. In the present review, we summarize the components of MSC-EVs and discuss the roles of MSC-EVs in different malignant diseases, including the related mechanisms that may account for their therapeutic potential. MSC-EVs open up a promising opportunity in the treatment of cancer with increased efficacy.

Chronic myeloid leukemia (CML) is a disease originated from malignant hematopoietic stem cell disorder. In CML, mesenchymal stem cells(MSC) have been changed in the bone marrow microenvironment, which can protect the leukemia cells from apoptosis induced by tyrosine kinase inhibitors (TKI) and lead to the resistance to TKI by the secretion of soluble factors, involvement in cell-cell adhesion, and so on. This review mainly focuses on the changes of the bone marrow mesenchymal stem cells in CML, as well as the role and mechanism of MSC in the CML resistance of TKI. The concrete probrems dicussing in this review are role of MSC in bone marrow microenviroment, characteristics of MSC in CML, the related mechanisms of MSC in drug resistance and so on.

The TSC1/2 heterodimer, a key upstream regulator of the mTOR, can inhibit the activation of mTOR, which plays a critical role in immune responses after bacterial infections. Monocytes are an innate immune cell type that have been shown to be involved in bacteremia. However, how the mTOR pathway is involved in the regulation of monocytes is largely unknown. In our study, TSC1 KO mice and WT mice were infected with E. coli. When compared to WT mice, we found higher mortality, greater numbers of bacteria, decreased expression of coactivators in monocytes, increased numbers of Tregs, and decreased numbers of effector T cells in TSC1 KO mice. Monocytes obtained from TSC1 KO mice produced more ROS, IL-6, IL-10, and TGF-β and less IL-1, IFN-γ, and TNF-α. Taken together, our results suggest that the inhibited immune functioning in TSC1 KO mice is influenced by mTORC1 activation in monocytes. The reduced expression of coactivators resulted in inhibited effector T cell proliferation. mTORC1-activated monocytes are harmful during bacterial infections. Therefore, inhibiting mTORC1 signaling through rapamycin administration could rescue the harmful aspects of an overactive immune response, and this knowledge provides a new direction for clinical therapy.