Metabolic determinants of leukocyte pathogenicity in neurological diseases

Runtsch, Marah C.; Ferrara, Giovanni Battista; Angiari, Stefano

doi:10.1111/jnc.15169

Cited by 13 publications

(24 citation statements)

References 305 publications

(426 reference statements)

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“…The CNS was once considered immune privileged based on the restrictive attributes of the blood brain barrier (BBB) ( 47 – 49 ). However, it is now clear that immune responses do occur in the CNS in a wide range of neurodegenerative and infectious diseases, and immune surveillance of the CNS takes place in the absence of pathology ( 50 – 52 ). Over the past decade, our laboratory has characterized the immune responses to S. aureus biofilm infection in both the CNS (craniotomy-associated infection) and periphery (prosthetic joint infection (PJI)) ( 19 , 40 , 41 , 46 , 53 – 56 ).…”

Section: Compartmentalization Of Immune Responses During Smentioning

confidence: 99%

Immunopathogenesis of Craniotomy Infection and Niche-Specific Immune Responses to Biofilm

et al. 2021

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Bacterial infections in the central nervous system (CNS) can be life threatening and often impair neurological function. Biofilm infection is a complication following craniotomy, a neurosurgical procedure that involves the removal and replacement of a skull fragment (bone flap) to access the brain for surgical intervention. The incidence of infection following craniotomy ranges from 1% to 3% with approximately half caused by Staphylococcus aureus (S. aureus). These infections present a significant therapeutic challenge due to the antibiotic tolerance of biofilm and unique immune properties of the CNS. Previous studies have revealed a critical role for innate immune responses during S. aureus craniotomy infection. Experiments using knockout mouse models have highlighted the importance of the pattern recognition receptor Toll-like receptor 2 (TLR2) and its adaptor protein MyD88 for preventing S. aureus outgrowth during craniotomy biofilm infection. However, neither molecule affected bacterial burden in a mouse model of S. aureus brain abscess highlighting the distinctions between immune regulation of biofilm vs. planktonic infection in the CNS. Furthermore, the immune responses elicited during S. aureus craniotomy infection are distinct from biofilm infection in the periphery, emphasizing the critical role for niche-specific factors in dictating S. aureus biofilm-leukocyte crosstalk. In this review, we discuss the current knowledge concerning innate immunity to S. aureus craniotomy biofilm infection, compare this to S. aureus biofilm infection in the periphery, and discuss the importance of anatomical location in dictating how biofilm influences inflammatory responses and its impact on bacterial clearance.

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Section: Compartmentalization Of Immune Responses During Smentioning

confidence: 99%

Immunopathogenesis of Craniotomy Infection and Niche-Specific Immune Responses to Biofilm

et al. 2021

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“…In recent years, the rapidly expanding field of immunometabolism has demonstrated that immune activation is controlled by the metabolic pathways needed to generate the energy and intermediates required for effector responses ( 26 , 48 , 49 ). The major pathways identified to date that dictate leukocyte function include glycolysis, the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), fatty acid oxidation and synthesis (FAO and FAS, respectively), the pentose phosphate pathway (PPP), and amino acid metabolism ( 50 ).…”

Section: Pathogenic and Immune Characteristics Of Cns Infectionsmentioning

confidence: 99%

“…Upon activation, astrocytes have been shown to undergo aerobic glycolysis to promote pro-inflammatory signals ( 54 , 63 ). Oligodendrocytes form the lipid-rich myelin supporting the propagation of neuronal action potentials, where cells respond to glutamatergic signals by increasing glycolysis to support axonal energy metabolism ( 26 , 66 ). The metabolic changes that occur in astrocytes and oligodendrocytes during CNS infection and how this shapes neuronal survival remain to be determined.…”

Section: Pathogenic and Immune Characteristics Of Cns Infectionsmentioning

confidence: 99%

“…Infiltrating leukocytes are the other key contributors to CNS infection. Macrophages, neutrophils, DCs, and natural killer (NK) cells are rapidly recruited into the infected CNS where they can influence glial activation through release of inflammatory cytokines and other factors such as ROS ( 25 , 26 , 67 – 69 ). Macrophages and monocytes are found in the CNS meningeal and perivascular interfaces as well as the infected brain and experience a metabolic shift from OXPHOS to glycolysis upon pro-inflammatory activation, similar to microglia ( 70 – 72 ).…”

Section: Pathogenic and Immune Characteristics Of Cns Infectionsmentioning

confidence: 99%

“…Engineered nanoparticle systems have emerged as a promising therapeutic path to circumvent BBB restrictions and provide targeted delivery of drugs to the CNS ( 23 , 24 ). Additionally, the concept of using immunometabolic modulation to treat neurological disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) has gained traction in recent years ( 25 , 26 ). We believe that using nanoparticle delivery systems with immunometabolic therapies could provide a paradigm shift for the successful treatment of life-threatening CNS infections.…”

Section: Introductionmentioning

confidence: 99%

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The Prospect of Nanoparticle Systems for Modulating Immune Cell Polarization During Central Nervous System Infection

et al. 2021

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The blood-brain barrier (BBB) selectively restricts the entry of molecules from peripheral circulation into the central nervous system (CNS) parenchyma. Despite this protective barrier, bacteria and other pathogens can still invade the CNS, often as a consequence of immune deficiencies or complications following neurosurgical procedures. These infections are difficult to treat since many bacteria, such as Staphylococcus aureus, encode a repertoire of virulence factors, can acquire antibiotic resistance, and form biofilm. Additionally, pathogens can leverage virulence factor production to polarize host immune cells towards an anti-inflammatory phenotype, leading to chronic infection. The difficulty of pathogen clearance is magnified by the fact that antibiotics and other treatments cannot easily penetrate the BBB, which requires extended regimens to achieve therapeutic concentrations. Nanoparticle systems are rapidly emerging as a promising platform to treat a range of CNS disorders. Nanoparticles have several advantages, as they can be engineered to cross the BBB with specific functionality to increase cellular and molecular targeting, have controlled release of therapeutic agents, and superior bioavailability and circulation compared to traditional therapies. Within the CNS environment, therapeutic actions are not limited to directly targeting the pathogen, but can also be tailored to modulate immune cell activation to promote infection resolution. This perspective highlights the factors leading to infection persistence in the CNS and discusses how novel nanoparticle therapies can be engineered to provide enhanced treatment, specifically through modulation of immune cell polarization.

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Dysregulation of Circulatory Levels of lncRNAs in Parkinson’s Disease

et al. 2022

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Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder. The emerging evidence suggests that long non-coding RNAs (lncRNAs) are involved in the pathogenesis of PD. In this study, we used gene expression pro les from GEO database to construct a PD-speci c lncRNA-miRNA-mRNA ceRNA network. Functional enrichment analysis suggested that ceRNA network might participate in the development of PD. The PPI network was constructed to identify these interactions between proteins translated by the screened differentially expressed genes, and the ceRNA subnetwork based on ve hub genes was set up. In a cohort of 32 PD patients and 31 healthy controls, the expression of 10 DElncRNAs (TTC3-AS1, LINC01259, ZMYND10-AS1, CHRM3-AS1, MYO16-AS1, AGBL5-IT1, HOTAIRM1, RABGAP1L-IT1, HLCS-IT1, and LINC00393) were further veri ed. Consistent with the microarray data, expression of LINC01259 was lower in total patients compared with total controls (P = 0.008), and other lncRNAs expression levels were not signi cantly different in the two groups. Intriguingly, such difference was only observed between male patients and male controls when dividing study participants based on their gender (P = 0.016). Receiver operating characteristic (ROC) curve analysis revealed that LINC01259 has diagnostic power of 0.694. Moreover, expression of LINC01259 was not correlated with age of patients, disease duration, disease stage, MDS-UPDRS and MMSE. The current study provides further evidence for dysregulation of lncRNAs in the circulation of PD patients and revealed LINC01259 has clinical potential as a biomarker for PD diagnosis.

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Metabolic determinants of leukocyte pathogenicity in neurological diseases

Cited by 13 publications

References 305 publications

Immunopathogenesis of Craniotomy Infection and Niche-Specific Immune Responses to Biofilm

Immunopathogenesis of Craniotomy Infection and Niche-Specific Immune Responses to Biofilm

The Prospect of Nanoparticle Systems for Modulating Immune Cell Polarization During Central Nervous System Infection

Dysregulation of Circulatory Levels of lncRNAs in Parkinson’s Disease

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