Graphene and the Immune System: A Romance of Many Dimensions

Graphene-based materials (GBMs) are emerging as attractive materials for biomedical applications. Understanding how these materials are perceived by and interact with the immune system is of fundamental importance. Phagocytosis is a major mechanism deployed by the immune system to remove pathogens, particles, and cellular debris. Here, we discuss recent studies on the interactions of GBMs with different phagocytic cells, including macrophages, neutrophils, and dendritic cells. The importance of assessing GBMs for endotoxin contamination is discussed as this may skew results. We also explore the role of the bio-corona for interactions of GBMs with immune cells. Finally, we highlight recent evidence for direct plasma membrane interactions of GBMs.

[1]  Mariya V. Khodakovskaya,et al.  Graphene and carbon nanotubes activate different cell surface receptors on macrophages before and after deactivation of endotoxins , 2017, Journal of applied toxicology : JAT.

[2]  Rui Liu,et al.  Crucial Role of Lateral Size for Graphene Oxide in Activating Macrophages and Stimulating Pro-inflammatory Responses in Cells and Animals. , 2015, ACS nano.

[3]  Andrew Emili,et al.  Protein corona fingerprinting predicts the cellular interaction of gold and silver nanoparticles. , 2014, ACS nano.

[4]  R. Jerala,et al.  Postulates for validating TLR4 agonists , 2015, European journal of immunology.

[5]  John D Lambris,et al.  Complement: a key system for immune surveillance and homeostasis , 2010, Nature Immunology.

[6]  T. Kirikae,et al.  Bacterial endotoxin: molecular relationships of structure to activity and function , 1994, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[7]  Polly Matzinger,et al.  Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses , 2004, Nature Reviews Immunology.

[8]  M. Prato,et al.  Science and technology roadmap for graphene, related two-dimensional crystals, and hybrid systems. , 2015, Nanoscale.

[9]  Per Axel Clausen,et al.  Long, needle-like carbon nanotubes and asbestos activate the NLRP3 inflammasome through a similar mechanism. , 2011, ACS nano.

[10]  Yang Li,et al.  Endotoxin contamination: a key element in the interpretation of nanosafety studies. , 2016, Nanomedicine.

[11]  Andrea Reboldi,et al.  Faculty Opinions recommendation of Inflammasomes: mechanism of assembly, regulation and signalling. , 2018, Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature.

[12]  Ruhong Zhou,et al.  Reduced Cytotoxicity of Graphene Nanosheets Mediated by Blood-Protein Coating. , 2015, ACS nano.

[13]  Agnes B Kane,et al.  Biological interactions of graphene-family nanomaterials: an interdisciplinary review. , 2012, Chemical research in toxicology.

[14]  Wei Wei,et al.  Surface-engineered graphene navigate divergent biological outcomes toward macrophages. , 2015, ACS applied materials & interfaces.

[15]  R. Steinman.  Decisions about dendritic cells: past, present, and future. , 2012, Annual review of immunology.

[16]  N. Bottini,et al.  Carbon nanotube-based nanocarriers: the importance of keeping it clean. , 2010, Journal of nanoscience and nanotechnology.

[17]  Huajian Gao,et al.  Graphene microsheets enter cells through spontaneous membrane penetration at edge asperities and corner sites , 2013, Proceedings of the National Academy of Sciences.

[18]  S M Moghimi,et al.  Factors controlling nanoparticle pharmacokinetics: an integrated analysis and perspective. , 2012, Annual review of pharmacology and toxicology.

[19]  Haiping Fang,et al.  Destructive extraction of phospholipids from Escherichia coli membranes by graphene nanosheets. , 2013, Nature nanotechnology.

[20]  S. Krämer,et al.  Particle size and activation threshold: a new dimension of danger signaling. , 2010, Blood.

[21]  Kostas Kostarelos,et al.  Culture Media Critically Influence Graphene Oxide Effects on Plasma Membranes , 2017 .

[22]  Meiying Wang,et al.  NADPH Oxidase-Dependent NLRP3 Inflammasome Activation and its Important Role in Lung Fibrosis by Multiwalled Carbon Nanotubes. , 2015, Small.

[23]  Egil Lien,et al.  NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals , 2010, Nature.

[24]  V. Dixit,et al.  Inflammasomes: mechanism of assembly, regulation and signalling , 2016, Nature Reviews Immunology.

[25]  T. Harrer,et al.  Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines , 2014, Nature Medicine.

[26]  Lin Zhao,et al.  Protein corona mitigates the cytotoxicity of graphene oxide by reducing its physical interaction with cell membrane. , 2015, Nanoscale.

[27]  R. Bishop.  Fundamentals of endotoxin structure and function. , 2005, Contributions to microbiology.

[28]  Jian Qin,et al.  The importance of an endotoxin-free environment during the production of nanoparticles used in medical applications. , 2006, Nano letters.

[29]  Rino Rappuoli,et al.  Alum adjuvanticity: Unraveling a century old mystery , 2008, European journal of immunology.

[30]  Stefan Tenzer,et al.  Rapid formation of plasma protein corona critically affects nanoparticle pathophysiology. , 2013, Nature nanotechnology.

[31]  J. Tait,et al.  Challenges and opportunities. , 1996, Journal of psychiatric and mental health nursing.

[32]  J. Millis.  Challenges ahead , 1998, Nature.

[33]  Bengt Fadeel,et al.  Classification framework for graphene-based materials. , 2014, Angewandte Chemie.

[34]  B. Alman,et al.  Phenotype Determines Nanoparticle Uptake by Human Macrophages from Liver and Blood. , 2017, ACS nano.

[35]  Jingyan Zhang,et al.  Vacuolization in Cytoplasm and Cell Membrane Permeability Enhancement Triggered by Micrometer-Sized Graphene Oxide. , 2015, ACS nano.

[36]  Lei Wang,et al.  Graphene oxide induces toll-like receptor 4 (TLR4)-dependent necrosis in macrophages. , 2013, ACS nano.

[37]  P. Kubes,et al.  An emerging role for neutrophil extracellular traps in noninfectious disease , 2017, Nature Medicine.

[38]  Katharina Landfester,et al.  Controlling the Stealth Effect of Nanocarriers through Understanding the Protein Corona. , 2016, Angewandte Chemie.

[39]  Bengt Fadeel,et al.  Detection of Endotoxin Contamination of Graphene Based Materials Using the TNF-α Expression Test and Guidelines for Endotoxin-Free Graphene Oxide Production , 2016, PloS one.

[40]  Bengt Fadeel,et al.  Biological interactions of carbon-based nanomaterials: From coronation to degradation. , 2016, Nanomedicine : nanotechnology, biology, and medicine.

[41]  T. Xia,et al.  Graphene Oxide Induced Perturbation to Plasma Membrane and Cytoskeletal Meshwork Sensitize Cancer Cells to Chemotherapeutic Agents. , 2017, ACS nano.

[42]  Franklin Kim,et al.  Graphene oxide sheets at interfaces. , 2010, Journal of the American Chemical Society.

[43]  A. Kraegeloh,et al.  Interference of silica nanoparticles with the traditional Limulus amebocyte lysate gel clot assay , 2014, Innate immunity.

[44]  A. Zychlinsky,et al.  NETs: a new strategy for using old weapons. , 2009, Trends in immunology.

[45]  Yong Hoon Joo,et al.  In vitro and in vivo comparison of the immunotoxicity of single- and multi-layered graphene oxides with or without pluronic F-127 , 2016, Scientific Reports.

[46]  Meiying Wang,et al.  Engineering an effective immune adjuvant by designed control of shape and crystallinity of aluminum oxyhydroxide nanoparticles. , 2013, ACS nano.

[47]  Peter Wick,et al.  Contamination of nanoparticles by endotoxin: evaluation of different test methods , 2012, Particle and Fibre Toxicology.

[48]  Lin Zhao,et al.  Potential toxicity of graphene to cell functions via disrupting protein-protein interactions. , 2015, ACS nano.

[49]  A. Zychlinsky,et al.  Neutrophil Extracellular Traps Kill Bacteria , 2004, Science.

[50]  F. Martinon,et al.  Gout-associated uric acid crystals activate the NALP3 inflammasome , 2006, Nature.

[51]  Meiying Wang,et al.  Use of a pro-fibrogenic mechanism-based predictive toxicological approach for tiered testing and decision analysis of carbonaceous nanomaterials. , 2015, ACS nano.

[52]  Andrij Holian,et al.  Extracellular HMGB1 regulates multi-walled carbon nanotube-induced inflammation in vivo , 2015, Nanotoxicology.

[53]  K. Novoselov,et al.  Exploring the Interface of Graphene and Biology , 2014, Science.

[54]  C. Li,et al.  Graphene Oxides Decorated with Carnosine as an Adjuvant To Modulate Innate Immune and Improve Adaptive Immunity in Vivo. , 2016, ACS nano.

[55]  Hongjie Dai,et al.  Single-walled carbon nanotube surface control of complement recognition and activation. , 2013, ACS nano.

[56]  Wei Chen,et al.  Improved In Vitro and In Vivo Biocompatibility of Graphene Oxide through Surface Modification: Poly(Acrylic Acid)-Functionalization is Superior to PEGylation. , 2016, ACS nano.

[57]  Sanjay Mathur,et al.  Hollow carbon spheres trigger inflammasome-dependent IL-1β secretion in macrophages , 2017 .

[58]  Sara Linse,et al.  Understanding the nanoparticle–protein corona using methods to quantify exchange rates and affinities of proteins for nanoparticles , 2007, Proceedings of the National Academy of Sciences.

[59]  Sebastian Hoffmann,et al.  International validation of novel pyrogen tests based on human monocytoid cells. , 2005, Journal of immunological methods.

[60]  Yu-Chen Hu,et al.  Simultaneous induction of autophagy and toll-like receptor signaling pathways by graphene oxide. , 2012, Biomaterials.

[61]  Kai Simons,et al.  Lipid Rafts As a Membrane-Organizing Principle , 2010, Science.

[62]  Noureddine Abidi,et al.  Wettability and surface free energy of graphene films. , 2009, Langmuir : the ACS journal of surfaces and colloids.

[63]  Iseult Lynch,et al.  Designing the nanoparticle-biomolecule interface for "targeting and therapeutic delivery". , 2012, Journal of controlled release : official journal of the Controlled Release Society.

[64]  K. Dawson,et al.  The Intracellular Destiny of the Protein Corona: A Study on its Cellular Internalization and Evolution. , 2016, ACS nano.

[65]  H. Hammad,et al.  Cutting Edge: Alum Adjuvant Stimulates Inflammatory Dendritic Cells through Activation of the NALP3 Inflammasome , 2008, The Journal of Immunology.

[66]  A. Aderem,et al.  Mechanisms of phagocytosis in macrophages. , 1999, Annual review of immunology.

[67]  A. Warnatsch,et al.  Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis , 2015, Science.

[68]  Marco Orecchioni,et al.  Molecular and Genomic Impact of Large and Small Lateral Dimension Graphene Oxide Sheets on Human Immune Cells from Healthy Donors , 2016, Advanced healthcare materials.

[69]  Debra L Laskin,et al.  Macrophages and tissue injury: agents of defense or destruction? , 2011, Annual review of pharmacology and toxicology.

[70]  Bengt Fadeel,et al.  Mechanisms of carbon nanotube-induced toxicity: focus on pulmonary inflammation. , 2013, Advanced drug delivery reviews.

[71]  Yachong Guo,et al.  Graphene Induces Formation of Pores That Kill Spherical and Rod-Shaped Bacteria. , 2015, ACS nano.

[72]  B. Luan,et al.  Graphene-Induced Pore Formation on Cell Membranes , 2017, Scientific Reports.

[73]  Barry Moran,et al.  Functionalization of carbon nanoparticles modulates inflammatory cell recruitment and NLRP3 inflammasome activation. , 2013, Small.

[74]  Marco P Monopoli,et al.  Biomolecular coronas provide the biological identity of nanosized materials. , 2012, Nature nanotechnology.

[75]  Richard A. Flavell,et al.  Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants , 2008, Nature.

[76]  Martyn F. Symmons,et al.  Assembly and localization of Toll-like receptor signalling complexes , 2014, Nature Reviews Immunology.

[77]  Gregg P. Kotchey.  Enzyme-catalyzed Degradation of Carbon Nanomaterials , 2013 .

[78]  Kai Yang,et al.  Functionalization of graphene oxide generates a unique interface for selective serum protein interactions. , 2013, ACS applied materials & interfaces.

[79]  Yan Wang,et al.  Stealth Immune Properties of Graphene Oxide Enabled by Surface-Bound Complement Factor H. , 2016, ACS nano.

[80]  Katharina Landfester,et al.  Protein adsorption is required for stealth effect of poly(ethylene glycol)- and poly(phosphoester)-coated nanocarriers. , 2016, Nature nanotechnology.

[81]  Marina A Dobrovolskaia,et al.  Evaluation of nanoparticle immunotoxicity. , 2009, Nature nanotechnology.

[82]  Malcolm L. H. Green,et al.  Complement activation and protein adsorption by carbon nanotubes. , 2006, Molecular immunology.

[83]  Marina A Dobrovolskaia,et al.  Ambiguities in applying traditional Limulus amebocyte lysate tests to quantify endotoxin in nanoparticle formulations. , 2010, Nanomedicine.

[84]  Jeffrey S. Reynolds,et al.  Graphene Oxide Attenuates Th2-Type Immune Responses, but Augments Airway Remodeling and Hyperresponsiveness in a Murine Model of Asthma , 2014, ACS nano.

[85]  William R. Dichtel,et al.  Graphene Oxide Nanosheets Stimulate Ruffling and Shedding of Mammalian Cell Plasma Membranes. , 2016, Chem.

[86]  D. Holdstock.  Past, present--and future? , 2005, Medicine, conflict, and survival.

[87]  Sanjay Mathur,et al.  Graphene oxide, but not fullerenes, targets immunoproteasomes and suppresses antigen presentation by dendritic cells. , 2013, Small.

[88]  Ruhong Zhou,et al.  PEGylated graphene oxide elicits strong immunological responses despite surface passivation , 2017, Nature Communications.

[89]  R. Ruoff,et al.  The chemistry of graphene oxide. , 2010, Chemical Society reviews.

[90]  Q. Wang,et al.  Neutrophils sense microbial size and selectively release neutrophil extracellular traps in response to large pathogens , 2014, Nature Immunology.

[91]  Carl Nathan,et al.  Neutrophils and immunity: challenges and opportunities , 2006, Nature Reviews Immunology.

[92]  N. Bovet,et al.  Soluble and immobilized graphene oxide activates complement system differently dependent on surface oxidation state. , 2016, Biomaterials.

[93]  Bengt Fadeel,et al.  It takes two to tango: Understanding the interactions between engineered nanomaterials and the immune system. , 2015, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[94]  Katharina Landfester,et al.  Differential uptake of functionalized polystyrene nanoparticles by human macrophages and a monocytic cell line. , 2011, ACS nano.

[95]  B. Lambrecht,et al.  Spontaneous Protein Adsorption on Graphene Oxide Nanosheets Allowing Efficient Intracellular Vaccine Protein Delivery. , 2016, ACS applied materials & interfaces.

[96]  J. Meng,et al.  Carbon Nanotubes Activate Limulus Amebocyte Lysate Coagulation by Interface Adsorption. , 2017, ACS applied materials & interfaces.

[97]  Sung Tae Kim,et al.  Regulation of Macrophage Recognition through the Interplay of Nanoparticle Surface Functionality and Protein Corona. , 2016, ACS nano.

[98]  Moreno Meneghetti,et al.  Evidencing the mask effect of graphene oxide: a comparative study on primary human and murine phagocytic cells. , 2013, Nanoscale.

[99]  G. Zeng,et al.  Biodegradation of Carbon Nanotubes, Graphene, and Their Derivatives. , 2017, Trends in biotechnology.

[100]  Liangzhu Feng,et al.  Functionalized graphene oxide serves as a novel vaccine nano-adjuvant for robust stimulation of cellular immunity. , 2016, Nanoscale.

[101]  J. M. Brauner,et al.  Nanoparticles size-dependently initiate self-limiting NETosis-driven inflammation , 2016, Proceedings of the National Academy of Sciences.

[102]  Ping Zhang,et al.  Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity , 2011, Nature Medicine.

[103]  Nunzio Bottini,et al.  Surface polyethylene glycol conformation influences the protein corona of polyethylene glycol-modified single-walled carbon nanotubes: potential implications on biological performance. , 2013, ACS nano.

[104]  Jack A. Elias,et al.  Acidic Mammalian Chitinase in Asthmatic Th2 Inflammation and IL-13 Pathway Activation , 2004, Science.

[105]  B. Fadeel,et al.  Macrophage activation status determines the internalization of mesoporous silica particles of different sizes: Exploring the role of different pattern recognition receptors. , 2017, Biomaterials.

[106]  R. Zhou,et al.  Binding of blood proteins to carbon nanotubes reduces cytotoxicity , 2011, Proceedings of the National Academy of Sciences.

[107]  S. A. Hasan,et al.  A natural vanishing act: the enzyme-catalyzed degradation of carbon nanomaterials. , 2012, Accounts of chemical research.

[108]  B. Hong,et al.  Prospects and Challenges of Graphene in Biomedical Applications , 2013, Advanced materials.

[109]  J Szebeni,et al.  Complement activation cascade triggered by PEG-PL engineered nanomedicines and carbon nanotubes: the challenges ahead. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[110]  Kenneth A. Dawson,et al.  Nanoparticle size and surface properties determine the protein corona with possible implications for biological impacts , 2008, Proceedings of the National Academy of Sciences.