Neuroprotection by Neurotropin through Crosstalk of Neurotrophic and Innate Immune Receptors in PC12 Cells

Infected or damaged tissues release multiple “alert” molecules such as alarmins and damage-associated molecular patterns (DAMPs) that are recognized by innate immune receptors, and induce tissue inflammation, regeneration, and repair. Recently, an extract from inflamed rabbit skin inoculated with vaccinia virus (Neurotropin®, NTP) was found to induce infarct tolerance in mice receiving permanent ischemic attack to the middle cerebral artery. Likewise, we report herein that NTP prevented the neurite retraction in PC12 cells by nerve growth factor (NGF) deprivation. This effect was accompanied by interaction of Fyn with high-affinity NGF receptor TrkA. Sucrose density gradient subcellular fractionation of NTP-treated cells showed heretofore unidentified membrane fractions with a high-buoyant density containing Trk, B subunit of cholera toxin-bound ganglioside, flotillin-1 and Fyn. Additionally, these new membrane fractions also contained Toll-like receptor 4 (TLR4). Inhibition of TLR4 function by TAK-242 prevented the formation of these unidentified membrane fractions and suppressed neuroprotection by NTP. These observations indicate that NTP controls TrkA-mediated signaling through the formation of clusters of new membrane microdomains, thus providing a platform for crosstalk between neurotrophic and innate immune receptors. Neuroprotective mechanisms through the interaction with innate immune systems may provide novel mechanism for neuroprotection.

Download Full-text

Innate immune receptors in type 1 diabetes: the relationship to cell death-associated inflammation

Biochemical Society Transactions ◽

10.1042/bst20200131 ◽

2020 ◽

Vol 48 (3) ◽

pp. 1213-1225 ◽

Cited By ~ 1

Author(s):

Tae Kang Kim ◽

Myung-Shik Lee

Keyword(s):

Innate Immunity ◽

Type 1 Diabetes ◽

Inflammatory Responses ◽

Critical Role ◽

Innate Immune ◽

Therapeutic Modalities ◽

Immune Receptors ◽

Molecular Patterns

The importance of innate immunity in host defense and inflammatory responses has been clearly demonstrated after the discovery of innate immune receptors such as Toll-like receptors (TLRs) or Nucleotide-binding oligomerization domain-containing protein (Nod)-like receptors (NLRs). Innate immunity also plays a critical role in diverse pathological conditions including autoimmune diseases such as type 1 diabetes (T1D). In particular, the role of a variety of innate immune receptors in T1D has been demonstrated using mice with targeted disruption of such innate immune receptors. Here, we discuss recent findings showing the role of innate immunity in T1D that were obtained mostly from studies of genetic mouse models of innate immune receptors. In addition, the role of innate immune receptors involved in the pathogenesis of T1D in sensing death-associated molecular patterns (DAMPs) released from dead cells or pathogen-associated molecular patterns (PAMPs) will also be covered. Elucidation of the role of innate immune receptors in T1D and the nature of DAMPs sensed by such receptors may lead to the development of new therapeutic modalities against T1D.

Download Full-text

Recognition of meningococcal molecular patterns by innate immune receptors

International Journal of Medical Microbiology ◽

10.1016/j.ijmm.2008.06.007 ◽

2009 ◽

Vol 299 (1) ◽

pp. 9-20 ◽

Cited By ~ 8

Author(s):

C SCHMITT ◽

A VILLWOCK ◽

O KURZAI

Keyword(s):

Innate Immune ◽

Immune Receptors ◽

Molecular Patterns

Download Full-text

Advances in Understanding Activation and Function of the NLRC4 Inflammasome

International Journal of Molecular Sciences ◽

10.3390/ijms22031048 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1048

Author(s):

Balamurugan Sundaram ◽

Thirumala-Devi Kanneganti

Keyword(s):

Immune Response ◽

Cell Death ◽

Innate Immune ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Immune Receptors ◽

Caspase 1 ◽

Cell Death Pathway ◽

Molecular Patterns

Innate immune receptors initiate a host immune response, or inflammatory response, upon detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Among the innate immune receptors, nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) play a pivotal role in detecting cytosolic PAMPs and DAMPs. Some NLRs can form a multiprotein cytosolic complex known as the inflammasome. Inflammasome activation triggers caspase-1–mediated cleavage of the pore-forming protein gasdermin D (GSDMD), which drives a form of inflammatory cell death called pyroptosis. Parallelly, activated caspase-1 cleaves immature cytokines pro–IL-1β and pro–IL-18 into their active forms, which can be released via GSDMD membrane pores. The NLR family apoptosis inhibitory proteins (NAIP)-NLR family caspase-associated recruitment domain-containing protein 4 (NLRC4) inflammasome is important for mounting an immune response against Gram-negative bacteria. NLRC4 is activated through NAIPs sensing type 3 secretion system (T3SS) proteins from Gram-negative bacteria, such as Salmonella Typhimurium. Mutations in NAIPs and NLRC4 are linked to autoinflammatory disorders in humans. In this review, we highlight the role of the NAIP/NLRC4 inflammasome in host defense, autoinflammatory diseases, cancer, and cell death. We also discuss evidence pointing to a role of NLRC4 in PANoptosis, which was recently identified as a unique inflammatory programmed cell death pathway with important physiological relevance in a range of diseases. Improved understanding of the NLRC4 inflammasome and its potential roles in PANoptosis paves the way for identifying new therapeutic strategies to target disease.

Download Full-text

Faculty Opinions recommendation of Inflammatory caspases are innate immune receptors for intracellular LPS.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718530133.793544987 ◽

2018 ◽

Author(s):

Jerrold Weiss

Keyword(s):

Innate Immune ◽

Immune Receptors ◽

Inflammatory Caspases

Download Full-text

NOD-Like Receptors: Guards of Cellular Homeostasis Perturbation during Infection

International Journal of Molecular Sciences ◽

10.3390/ijms22136714 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6714

Author(s):

Gang Pei ◽

Anca Dorhoi

Keyword(s):

Immune System ◽

Innate Immune System ◽

Current Knowledge ◽

Protein Translation ◽

Innate Immune ◽

Cellular Homeostasis ◽

Translation Block ◽

Cytoskeleton Disruption ◽

Molecular Patterns ◽

Fine Tune

The innate immune system relies on families of pattern recognition receptors (PRRs) that detect distinct conserved molecular motifs from microbes to initiate antimicrobial responses. Activation of PRRs triggers a series of signaling cascades, leading to the release of pro-inflammatory cytokines, chemokines and antimicrobials, thereby contributing to the early host defense against microbes and regulating adaptive immunity. Additionally, PRRs can detect perturbation of cellular homeostasis caused by pathogens and fine-tune the immune responses. Among PRRs, nucleotide binding oligomerization domain (NOD)-like receptors (NLRs) have attracted particular interest in the context of cellular stress-induced inflammation during infection. Recently, mechanistic insights into the monitoring of cellular homeostasis perturbation by NLRs have been provided. We summarize the current knowledge about the disruption of cellular homeostasis by pathogens and focus on NLRs as innate immune sensors for its detection. We highlight the mechanisms employed by various pathogens to elicit cytoskeleton disruption, organelle stress as well as protein translation block, point out exemplary NLRs that guard cellular homeostasis during infection and introduce the concept of stress-associated molecular patterns (SAMPs). We postulate that integration of information about microbial patterns, danger signals, and SAMPs enables the innate immune system with adequate plasticity and precision in elaborating responses to microbes of variable virulence.

Download Full-text

Effects of innate immune receptor stimulation on extracellular α-synuclein uptake and degradation by brain resident cells

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00562-6 ◽

2021 ◽

Author(s):

Changyoun Kim ◽

Somin Kwon ◽

Michiyo Iba ◽

Brian Spencer ◽

Edward Rockenstein ◽

...

Keyword(s):

Degradation Kinetics ◽

Morphological Changes ◽

Direct Interaction ◽

Innate Immune ◽

Pathological Feature ◽

Tlr2 Expression ◽

Immune Receptors ◽

Age Related ◽

Stimulation Of

AbstractSynucleinopathies are age-related neurological disorders characterized by the progressive deposition of α-synuclein (α-syn) aggregates and include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Although cell-to-cell α-syn transmission is thought to play a key role in the spread of α-syn pathology, the detailed mechanism is still unknown. Neuroinflammation is another key pathological feature of synucleinopathies. Previous studies have identified several immune receptors that mediate neuroinflammation in synucleinopathies, such as Toll-like receptor 2 (TLR2). However, the species of α-syn aggregates varies from study to study, and how different α-syn aggregate species interact with innate immune receptors has yet to be addressed. Therefore, we investigated whether innate immune receptors can facilitate the uptake of different species of α-syn aggregates. Here, we examined whether stimulation of TLRs could modulate the cellular uptake and degradation of α-syn fibrils despite a lack of direct interaction. We observed that stimulation of TLR2 in vitro accelerated α-syn fibril uptake in neurons and glia while delaying the degradation of α-syn in neurons and astrocytes. Internalized α-syn was rapidly degraded in microglia regardless of whether TLR2 was stimulated. However, cellular α-syn uptake and degradation kinetics were not altered by TLR4 stimulation. In addition, upregulation of TLR2 expression in a synucleinopathy mouse model increased the density of Lewy-body-like inclusions and induced morphological changes in microglia. Together, these results suggest that cell type-specific modulation of TLR2 may be a multifaceted and promising therapeutic strategy for synucleinopathies; inhibition of neuronal and astroglial TLR2 decreases pathogenic α-syn transmission, but activation of microglial TLR2 enhances microglial extracellular α-syn clearance.

Download Full-text

Molecular heterogeneity of mouse duodenal alkaline phosphatase. Association of lipids and peptides

Biochemical Journal ◽

10.1042/bj1410093 ◽

1974 ◽

Vol 141 (1) ◽

pp. 93-101 ◽

Cited By ~ 19

Author(s):

P. R. V. Nayudu ◽

Fraser B. Hercus

Keyword(s):

Alkaline Phosphatase ◽

Gradient Centrifugation ◽

Polyacrylamide Gel Electrophoresis ◽

Buoyant Density ◽

Sucrose Density Gradient ◽

Molar Ratio ◽

Molecular Forms ◽

Partial Specific Volume ◽

Molecular Heterogeneity ◽

Sucrose Density Gradient Centrifugation

Polyacrylamide-gel electrophoresis and Bio-Gel P-300 molecular-sieve chromatography of mouse duodenal alkaline phosphatase demonstrates its molecular heterogeneity, which, in a kinetic sense, is manifest also in the differential relative velocities of the heterogeneous forms of the enzyme with two substrates, phenylphosphate and β-glycerophosphate. Different treatments that eliminate most of the electrophoretic and chromatographic variability of the enzyme also decrease the velocities with both substrates so that the molar ratio of hydrolysis of one substrate relative to the other is also altered to a low but stable value. Concomitant with these changes, lipids and peptides are dissociated from the enzyme. The lipids are tentatively identified as a sterol and phospholipids. The peptides have an average composition of four to six amino acids and appear to be strongly electropositive. The conditions of dissociation suggest that their binding to the enzyme is non-covalent and predominantly based on hydrophobic and ionic bonding. The concept of lipid and peptide association would suggest prima facie differential molecular weights as a factor in the observed electrophoretic and chromatographic heterogeneity. However, the molecular forms of the enzyme with differences in elution volume equivalent to more than one-half the void volume of the Bio-Gel P-300 column, or even enzyme fractions dissociated from the lipids and peptides compared with undissociated portions, do not show any differences in sedimentation on sucrose-density-gradient centrifugation. This may be because the alterations in molecular weight owing to binding of small molecules are too small to be detected by this method. Alternatively, since lipids are involved, the binding may alter the partial specific volume in such a way that the buoyant density is not significantly altered.

Download Full-text

Analytical Subcellular Fractionation Studies on Rat Liver and on Isolated Jejunal Enterocytes with Special Reference to the Separation of Lysosomes, Peroxisomes and Mitochondria

Clinical Science ◽

10.1042/cs0500355 ◽

1976 ◽

Vol 50 (5) ◽

pp. 355-366 ◽

Cited By ~ 2

Author(s):

T. J. Peters ◽

H. Shio

Keyword(s):

Rat Liver ◽

Sucrose Density Gradient ◽

Subcellular Fractionation ◽

Low Molecular Weight ◽

Rat Jejunum ◽

Marker Enzymes ◽

Good Separation ◽

Subcellular Organelles ◽

Rat Liver Cells ◽

Isopycnic Centrifugation

1. Enterocytes were isolated from rat jejunum and characterized morphologically. 2. Attempts to separate the enterocyte subcellular organelles, characterized by their marker enzymes, with isopycnic centrifugation were unsuccessful but good separation of peroxisomes, lysosomes and mitochondria was achieved by sedimentation through a shallow sucrose density gradient with a superimposed inverse gradient of low-molecular-weight dextran. 3. The properties and enzyme activities of the principal subcellular organelles in rat liver cells and enterocytes were compared.

Download Full-text