The Interactions between Nanoparticles and the Innate Immune System from a Nanotechnologist Perspective

The immune system contributes to maintaining the body’s functional integrity through its two main functions: recognizing and destroying foreign external agents (invading microorganisms) and identifying and eliminating senescent cells and damaged or abnormal endogenous entities (such as cellular debris or misfolded/degraded proteins). Accordingly, the immune system can detect molecular and cellular structures with a spatial resolution of a few nm, which allows for detecting molecular patterns expressed in a great variety of pathogens, including viral and bacterial proteins and bacterial nucleic acid sequences. Such patterns are also expressed in abnormal cells. In this context, it is expected that nanostructured materials in the size range of proteins, protein aggregates, and viruses with different molecular coatings can engage in a sophisticated interaction with the immune system. Nanoparticles can be recognized or passed undetected by the immune system. Once detected, they can be tolerated or induce defensive (inflammatory) or anti-inflammatory responses. This paper describes the different modes of interaction between nanoparticles, especially inorganic nanoparticles, and the immune system, especially the innate immune system. This perspective should help to propose a set of selection rules for nanosafety-by-design and medical nanoparticle design.

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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.

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Therapeutic Interventions into Innate Immune Diseases by Means of Aptamers

Pharmaceutics ◽

10.3390/pharmaceutics12100955 ◽

2020 ◽

Vol 12 (10) ◽

pp. 955

Author(s):

Farzana Yasmeen ◽

Hana Seo ◽

Nasir Javaid ◽

Moon Suk Kim ◽

Sangdun Choi

Keyword(s):

Pattern Recognition ◽

Immune System ◽

Crucial Role ◽

Innate Immune System ◽

Innate Immune ◽

Therapeutic Interventions ◽

Immune System Diseases ◽

Target Molecules ◽

Molecular Patterns ◽

Recognition Receptor

The immune system plays a crucial role in the body’s defense system against various pathogens, such as bacteria, viruses, and parasites, as well as recognizes non-self- and self-molecules. The innate immune system is composed of special receptors known as pattern recognition receptors, which play a crucial role in the identification of pathogen-associated molecular patterns from diverse microorganisms. Any disequilibrium in the activation of a particular pattern recognition receptor leads to various inflammatory, autoimmune, or immunodeficiency diseases. Aptamers are short single-stranded deoxyribonucleic acid or ribonucleic acid molecules, also termed “chemical antibodies,” which have tremendous specificity and affinity for their target molecules. Their features, such as stability, low immunogenicity, ease of manufacturing, and facile screening against a target, make them preferable as therapeutics. Immune-system–targeting aptamers have a great potential as a targeted therapeutic strategy against immune diseases. This review summarizes components of the innate immune system, aptamer production, pharmacokinetic characteristics of aptamers, and aptamers related to innate-immune-system diseases.

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Case Report: Innate Immune System Challenge Unleashes Paraneoplastic Neurological Autoimmunity

Frontiers in Neurology ◽

10.3389/fneur.2020.598894 ◽

2020 ◽

Vol 11 ◽

Author(s):

Mingqin Zhu ◽

Yuetao Ma ◽

Anastasia Zekeridou ◽

Vanda A. Lennon

Keyword(s):

Immune System ◽

Innate Immune System ◽

Protein Complexes ◽

Innate Immune ◽

Neurological Symptoms ◽

Autoimmune Response ◽

Tnf Α ◽

Bladder Instillation ◽

Molecular Patterns ◽

Symptoms And Signs

Paraneoplastic autoimmune neurological disorders reflect tumor-initiated immune responses against onconeural antigens. Symptoms and signs can affect the central and/or peripheral nervous systems, neuromuscular junction or muscle, and typically evolve subacutely before an underlying neoplasm is discovered. We describe four patients whose neurological symptoms were precipitated by potent innate immune system challenges: bladder instillation of BCG, tick bite and an “alternative cancer therapy” with bacterial extracts and TNF-α. We hypothesize that a tumor-initiated autoimmune response (evidenced by autoantibody profiles), pre-dating the immune system challenge, was unmasked or amplified in these patients by cytokines released systemically from innate immune cells activated by microbial pathogen-associated molecular patterns (PAMPs). The resultant upregulation of cognate onconeural peptides as MHC1 protein complexes on neural cell surfaces would render those cells susceptible to killing by CD8+ T cells, thus precipitating the patient's neurological symptoms.

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Effect of Hypoglycemia on Inflammatory Responses and the Response to Low-Dose Endotoxemia in Humans

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2018-01168 ◽

2018 ◽

Vol 104 (4) ◽

pp. 1187-1199 ◽

Cited By ~ 15

Author(s):

Ahmed Iqbal ◽

Lynne R Prince ◽

Peter Novodvorsky ◽

Alan Bernjak ◽

Mark R Thomas ◽

...

Keyword(s):

Cardiovascular Risk ◽

Immune System ◽

Innate Immune System ◽

Low Dose ◽

Inflammatory Responses ◽

Platelet Reactivity ◽

Innate Immune ◽

Endotoxin Challenge ◽

Intermediate Monocytes

Abstract Context Hypoglycemia is emerging as a risk for cardiovascular events in diabetes. We hypothesized that hypoglycemia activates the innate immune system, which is known to increase cardiovascular risk. Objective To determine whether hypoglycemia modifies subsequent innate immune system responses. Design and Setting Single-blinded, prospective study of three independent parallel groups. Participants and Interventions Twenty-four healthy participants underwent either a hyperinsulinemic-hypoglycemic (2.5 mmol/L), euglycemic (6.0 mmol/L), or sham-saline clamp (n = 8 for each group). After 48 hours, all participants received low-dose (0.3 ng/kg) intravenous endotoxin. Main Outcome Measures We studied in-vivo monocyte mobilization and monocyte-platelet interactions. Results Hypoglycemia increased total leukocytes (9.98 ± 1.14 × 109/L vs euglycemia 4.38 ± 0.53 × 109/L, P < 0.001; vs sham-saline 4.76 ± 0.36 × 109/L, P < 0.001) (mean ± SEM), mobilized proinflammatory intermediate monocytes (42.20 ± 7.52/μL vs euglycemia 20.66 ± 3.43/μL, P < 0.01; vs sham-saline 26.20 ± 3.86/μL, P < 0.05), and nonclassic monocytes (36.16 ± 4.66/μL vs euglycemia 12.72 ± 2.42/μL, P < 0.001; vs sham-saline 19.05 ± 3.81/μL, P < 0.001). Following hypoglycemia vs euglycemia, platelet aggregation to agonist (area under the curve) increased (73.87 ± 7.30 vs 52.50 ± 4.04, P < 0.05) and formation of monocyte-platelet aggregates increased (96.05 ± 14.51/μL vs 49.32 ± 6.41/μL, P < 0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51 ± 1.42/μL vs euglycemia 4.19 ± 1.08/μL, P < 0.05; vs sham-saline 3.81± 1.42/μL, P < 0.05) and nonclassic monocytes (9.53 ± 1.08/μL vs euglycemia 2.86 ± 0.72/μL, P < 0.01; vs sham-saline 3.08 ± 1.01/μL, P < 0.05), with platelets compared with controls. Hypoglycemia led to greater leukocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96 ± 0.97 vs euglycemia 8.21 ± 0.85 × 109/L, P < 0.05). Conclusions Hypoglycemia mobilizes monocytes, increases platelet reactivity, promotes interaction between platelets and proinflammatory monocytes, and potentiates the subsequent immune response to endotoxin. These changes may contribute to increased cardiovascular risk observed in people with diabetes.

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Bacterial cell wall macroamphiphiles: Pathogen-/microbe-associated molecular patterns detected by mammalian innate immune system

Biochimie ◽

10.1016/j.biochi.2012.06.007 ◽

2013 ◽

Vol 95 (1) ◽

pp. 33-42 ◽

Cited By ~ 46

Author(s):

Aurélie Ray ◽

Marlène Cot ◽

Germain Puzo ◽

Martine Gilleron ◽

Jérôme Nigou

Keyword(s):

Cell Wall ◽

Immune System ◽

Bacterial Cell ◽

Innate Immune System ◽

Bacterial Cell Wall ◽

Innate Immune ◽

Molecular Patterns

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Role of Toll-like receptors in liver health and disease

Clinical Science ◽

10.1042/cs20110065 ◽

2011 ◽

Vol 121 (10) ◽

pp. 415-426 ◽

Cited By ~ 48

Author(s):

Ruth Broering ◽

Mengji Lu ◽

Joerg F. Schlaak

Keyword(s):

Immune System ◽

Liver Disease ◽

Innate Immune System ◽

Innate Immune ◽

Toll Like Receptors ◽

Evolutionarily Conserved ◽

Liver Health ◽

Health And Disease ◽

Molecular Patterns

TLRs (Toll-like receptors), as evolutionarily conserved germline-encoded pattern recognition receptors, have a crucial role in early host defence by recognizing so-called PAMPs (pathogen-associated molecular patterns) and may serve as an important link between innate and adaptive immunity. In the liver, TLRs play an important role in the wound healing and regeneration processes, but they are also involved in the pathogenesis and progression of various inflammatory liver diseases, including autoimmune liver disease, alcoholic liver disease, non-alcoholic steatohepatitis, fibrogenesis, and chronic HBV (hepatitis B virus) and HCV (hepatitis C virus) infection. Hepatitis viruses have developed different evading strategies to subvert the innate immune system. Thus recent studies have suggested that TLR-based therapies may represent a promising approach in the treatment in viral hepatitis. The present review focuses on the role of the local innate immune system, and TLRs in particular, in the liver.

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Toll-like receptors and hypertension

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00194.2014 ◽

2014 ◽

Vol 307 (5) ◽

pp. R501-R504 ◽

Cited By ~ 27

Author(s):

Madhu V. Singh ◽

François M. Abboud

Keyword(s):

Immune System ◽

Innate Immune System ◽

Expression Patterns ◽

Adaptor Proteins ◽

Nuclear Factor Κb ◽

Innate Immune ◽

Toll Like Receptors ◽

Cardiovascular Damage ◽

Inflammatory Processes ◽

Molecular Patterns

Hypertension and associated inflammatory processes that accelerate cardiovascular damage are regulated by the innate immune system. Toll-like receptors (TLR) are major components of the innate immune system that recognize endogenous damage-associated molecular patterns to activate prominent inflammatory signaling including activation of nuclear factor-κB (NF-κB). However, the role of TLR in the etiology of hypertension is not well understood. TLR signaling is dependent on adaptor proteins that, along with the TLR expression patterns, confer specificity of the inflammatory response and its pathological targets. Here we review the conceptual framework of how TLR and their adaptor proteins may differentially affect hypertension and cardiac hypertrophy by different stimuli.

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In Vivo Discrimination of Type 3 Secretion System-Positive and -Negative Pseudomonas aeruginosa via a Caspase-1-Dependent Pathway

Infection and Immunity ◽

10.1128/iai.00744-10 ◽

2010 ◽

Vol 78 (11) ◽

pp. 4744-4753 ◽

Cited By ~ 21

Author(s):

Tamding Wangdi ◽

Lilia A. Mijares ◽

Barbara I. Kazmierczak

Keyword(s):

Pseudomonas Aeruginosa ◽

Immune System ◽

Innate Immune System ◽

Interleukin 1 ◽

Innate Immune ◽

Secretion Systems ◽

Caspase 1 ◽

Molecular Patterns ◽

Type 3

ABSTRACT Microbe-associated molecular patterns are recognized by Toll-like receptors of the innate immune system. This recognition enables a rapid response to potential pathogens but does not clearly provide a way for the innate immune system to discriminate between virulent and avirulent microbes. We find that pulmonary infection of mice with type 3 translocation-competent Pseudomonas aeruginosa triggers a rapid inflammatory response, while infection with isogenic translocation-deficient mutants does not. Discrimination between translocon-positive and -negative bacteria requires caspase-1 activity in bone marrow-derived cells and interleukin-1 receptor signaling. Thus, the activation of caspase-1 by bacteria expressing type 3 secretion systems allows for rapid recognition of bacteria expressing conserved functions associated with virulence.

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Combinational clustering of receptors following stimulation by bacterial products determines lipopolysaccharide responses

Biochemical Journal ◽

10.1042/bj20040172 ◽

2004 ◽

Vol 381 (2) ◽

pp. 527-536 ◽

Cited By ~ 107

Author(s):

Martha TRIANTAFILOU ◽

Klaus BRANDENBURG ◽

Shoichi KUSUMOTO ◽

Koichi FUKASE ◽

Alan MACKIE ◽

...

Keyword(s):

Immune Response ◽

Immune System ◽

Innate Immune System ◽

Imaging Techniques ◽

Innate Immune ◽

Surface Receptors ◽

Wide Range ◽

Species Specific ◽

Receptor Clusters ◽

Molecular Patterns

The innate immune system has the capacity to recognize a wide range of pathogens based on conserved PAMPs (pathogen-associated molecular patterns). In the case of bacterial LPS (lipopolysaccharide) recognition, the best studied PAMP, it has been shown that the innate immune system employs at least three cell-surface receptors: CD14, TLR4 (Toll-like receptor 4) and MD-2 protein. CD14 binds LPS from Enterobacteriaceae and then transfers it to MD-2, leading to TLR4 aggregation and signal transduction. LPS analogues such as lipid IVa seem to act as LPS antagonists in human cells, but exhibit LPS mimetic activity in mouse cells. Although TLR4 has been shown to be involved in this species-specific discrimination, the mechanism by which this is achieved has not been elucidated. The questions that remain are how the innate immune system can discriminate between LPS from different bacteria as well as different LPS analogues, and whether or not the structure of LPS affects its interaction with the CD14–TLR4–MD-2 cluster. Is it possible that the ‘shape’ of LPS induces the formation of different receptor clusters, and thus a different immune response? In the present study, we demonstrate using biochemical as well as fluorescence-imaging techniques that different LPS analogues trigger the recruitment of different receptors within microdomains. The composition of each receptor cluster as well as the number of TLR4 molecules that are recruited within the cluster seem to determine whether an immune response will be induced or inhibited.

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Toll-like receptors and damage-associated molecular patterns: novel links between inflammation and hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00328.2013 ◽

2014 ◽

Vol 306 (2) ◽

pp. H184-H196 ◽

Cited By ~ 105

Author(s):

Cameron G. McCarthy ◽

Styliani Goulopoulou ◽

Camilla F. Wenceslau ◽

Kathryn Spitler ◽

Takayuki Matsumoto ◽

...

Keyword(s):

Immune System ◽

Innate Immune System ◽

Cell Injury ◽

Receptor Activation ◽

Innate Immune ◽

Immune System Activation ◽

System Activation ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

Low-grade systemic inflammation is a common manifestation of hypertension; however, the exact mechanisms that initiate this pathophysiological response, thereby contributing to further increases in blood pressure, are not well understood. Aberrant vascular inflammation and reactivity via activation of the innate immune system may be the first step in the pathogenesis of hypertension. One of the functions of the innate immune system is to recognize and respond to danger. Danger signals can arise from not only pathogenic stimuli but also endogenous molecules released following cell injury and/or death [damage-associated molecular patterns (DAMPs)]. In the short-term, activation of the innate immune system is beneficial in the vasculature by providing cytoprotective mechanisms and facilitating tissue repair following injury or infection. However, sustained or excessive immune system activation, such as in autoimmune diseases, may be deleterious and can lead to maladaptive, irreversible changes to vascular structure and function. An initial source of DAMPs that enter the circulation to activate the innate immune system could arise from modest elevations in peripheral vascular resistance. These stimuli could subsequently lead to ischemic- or pressure-induced events aggravating further cell injury and/or death, providing more DAMPs for innate immune system activation. This review will address and critically evaluate the current literature on the role of the innate immune system in hypertension pathogenesis. The role of Toll-like receptor activation on somatic cells of the vasculature in response to the release of DAMPs and the consequences of this activation on inflammation, vasoreactivity, and vascular remodeling will be specifically discussed.

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