Extracellular Acidosis Is a Novel Danger Signal Alerting Innate Immunity via the NLRP3 Inflammasome

Rajamäki, Kristiina; Nordström, Tommy; Nurmi, Katariina; Åkerman, Karl E.O.; Kovanen, Petri T.; Öörni, Katariina; Eklund, Kari K.

doi:10.1074/jbc.m112.426254

Cited by 287 publications

(259 citation statements)

References 70 publications

(85 reference statements)

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“…Thus, in the therapeutic context of magnetically targeted drug or cell delivery as a therapeutic strategy for preventing arterial restenosis (35), our experiments offer several important observations. The increased rates of MNP disassembly in an acidified semisolid environment and in dividing smooth muscle cells suggest that the degradation of the respective fractions of the arterial wall-localized MNPs, i.e., those immobilized in the extracellular matrix or taken up by neointimal cells, may occur substantially faster early in the healing phase, characterized by rapid cell proliferation and inflammation, which may cause acidification of the local microenvironment (36). At the same time, it may be predicted that local delivery of antirestenotic drugs inhibiting the proliferation of the neointimal cells can reverse the accelerated MNP processing and slow the degradation of the cell-associated MNP fraction.…”

Section: Discussionmentioning

confidence: 99%

Real-time analysis of composite magnetic nanoparticle disassembly in vascular cells and biomimetic media

Tengood

Alferiev

Zhang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The fate of nanoparticle (NP) formulations in the multifaceted biological environment is a key determinant of their biocompatibility and therapeutic performance. An understanding of the degradation patterns of different types of clinically used and experimental NP formulations is currently incomplete, posing an unmet need for novel analytical tools providing unbiased quantitative measurements of NP disassembly directly in the medium of interest and in conditions relevant to specific therapeutic/ diagnostic applications. In the present study, this challenge was addressed with an approach enabling real-time in situ monitoring of the integrity status of NPs in cells and biomimetic media using Förster resonance energy transfer (FRET). Disassembly of polylactidebased magnetic NPs (MNPs) was investigated in a range of model biomimetic media and in cultured vascular cells using an experimentally established quantitative correlation between particle integrity and FRET efficiency controlled through adjustments in the spectral overlap between two custom-synthesized polylactide-fluorophore (boron dipyrromethene) conjugates incorporated in MNPs. The results suggest particle disassembly governed by diffusion-reaction processes with kinetics strongly dependent on conditions promoting release of oligomeric fragments from the particle matrix. Thus, incubation in gels simulating the extracellular environment and in protein-rich serum resulted in notably lower and higher MNP decomposition rates, respectively, compared with nonviscous liquid buffers. The diffusion-reaction mechanism also is consistent with a significant cell growth-dependent acceleration of MNP processing in dividing vs. contact-inhibited vascular cells. The FRET-based analytical strategy and experimental results reported herein may facilitate the development and inform optimization of biodegradable nanocarriers for cell and drug delivery applications.nanoparticle degradation | direct assay | endothelial cell | smooth muscle cell | restenosis N anoparticles (NPs) of different compositions and designs are emerging as versatile diagnostic tools and promising carriers for delivery of small molecule drugs and biotherapeutics (1, 2). Among the prerequisites for their safe and effective use, an understanding of the fate of NPs intended for diagnostic or therapeutic applications is an obvious requirement, as it ensures the absence of acute or chronic toxicity caused by foreign materials retained in the body (3). Biodegradation of NPs developed as drug delivery carriers also plays a key role in their therapeutic performance by contributing to the biodistribution and fate of the cargo; thus, it is of essential importance for optimizing the site specificity and duration of the pharmacological effect for a given application (4).Despite the recognized need for definitive studies of NP degradation and factors governing its kinetics (5), investigative strategies providing reliable in situ measurements of NP disassembly are lacking. The few in vitro studies examining the stabili...

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Section: Discussionmentioning

confidence: 99%

Real-time analysis of composite magnetic nanoparticle disassembly in vascular cells and biomimetic media

Tengood

Alferiev

Zhang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…It is noteworthy that keratins are not only expressed inside cells, they are also found on the surface of some cell types such as carcinoma cells (30,(48)(49)(50). Evidence shows that extracellular acidification is usually associated with inflammation and tumorigenesis and is treated as a danger signal by the immune system (51)(52)(53). Therefore, DEC205 may be able to recognize nonapoptotic cells in these cases and act as an enhanced version among scavenging receptors in acidified regions (54,55).…”

Section: Discussionmentioning

confidence: 99%

Keratin mediates the recognition of apoptotic and necrotic cells through dendritic cell receptor DEC205/CD205

Cao

Chang

Shi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Clearance of dead cells is critical for maintaining homeostasis and prevents autoimmunity and inflammation. When cells undergo apoptosis and necrosis, specific markers are exposed and recognized by the receptors on phagocytes. DEC205 (CD205) is an endocytotic receptor on dendritic cells with antigen presentation function and has been widely used in immune therapies for vaccine generation. It has been shown that human DEC205 recognizes apoptotic and necrotic cells in a pH-dependent fashion. However, the natural ligand(s) of DEC205 remains unknown. Here we find that keratins are the cellular ligands of human DEC205. DEC205 binds to keratins specifically at acidic, but not basic, pH through its N-terminal domains. Keratins form intermediate filaments and are important for maintaining the strength of cells and tissues. Our results suggest that keratins also function as cell markers of apoptotic and necrotic cells and mediate a pH-dependent pathway for the immune recognition of dead cells. T he immune system is responsible for removing self-antigens such as dead cells to maintain tissue homeostasis and prevent autoimmunity (1-3). Dead cells are recognized and engulfed by phagocytes through their cell surface receptors (4), leading to either immune activation or tolerance (5-8). A number of receptors have been found to be able to mediate the clearance of dead cells (3); for example, CD14 (9), CD36 (10), integrin (11), PtdSerR (12), CLEC9A (13-15), and TIM receptor family members (16). Among known dead cell markers, phosphatidylserine (PS) is the most common one that can be recognized by several receptors such as CD36, PtdSerR, and TIM receptors, and acts as an "eatme" signal for phagocytes mediating dead cell clearance (4). Other than PS, several cellular proteins have also been found to be able to perform the similar function. For example, actin filaments can be recognized by CLEC9A as a damaged cell marker (13, 15). The recognition of different dead cell markers by phagocytes provides an efficient way to remove cell debris completely.Keratins are important cytoskeletal components and form intermediate filaments in cytoplasm. There are 54 known members in the keratin family that are divided into two types based on their isoelectric points and sequences (17). Keratin monomers can assemble into bundles first and then form fibrous filaments ∼10 nm in diameter, which act as a scaffold and provide mechanical support for maintaining the strength and toughness of cells and tissues (18,19). Recently, evidence has accumulated showing that keratins play physiological roles in addition to their structural functions, for example, in cell growth, proliferation, mobility, apoptosis, and tumorigenesis (18,20,21). DEC205 (CD205 or Ly75, molecular mass of 205 kDa) is an endocytotic receptor highly expressed on dendritic cells and thymic epithelial cells (8,22) and capable of inducing either tolerance or immunity in the absence or presence of inflammatory stimuli (23). DEC205 belongs to the mannose receptor family (24), which includes...

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“…local ischemia, hypoxia, cholesterol crystals accumulated in vascular wall, necrotic cells, and histones, might act both as priming signals for IL-1β production by and trigger for neutrophils to release NETs via represent an endogenous danger signal that activates Nrf2 and the NLRP3 inflammasome (Freigang et al, 2011;Nahrendorf and Swirski, 2015;Warnatsch et al, 2015). All these could prime macrophages for cytokine release, activating Th17 cells that amplify immune cell recruitment in atherosclerotic plaques and induce microvascular inflammation that leads to vasculopathy (Allam et al, 2013;Rajamäki et al, 2010;Rajamaki et al, 2013). Overall, spontaneous NET-forming neutrophils may assist not only in the innate immune defense against different pathogens, but in early multicellular inflammatory reaction attenuating vascular damage and early stage of atherosclerosis.…”

Section: Spontaneous / Inducible Ne-tosis In Diabetes-related Vasculomentioning

confidence: 99%

Is the neutrophil extracellular trap-driven microvascular inflammation essential for diabetes vasculopathy?

Berezin

2016

Biomed Res Ther

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Abstract-The neutrophil extracellular traps (NETs) are defined as an extensive web consisting decondensed chromatin, which is released from activated neutrophils, as well as cytotoxic proteins, histones and microbicidal proteases that cause tissue damage. NETs contribute to endothelial damage, inflammation, thrombosis, platelet aggregation, ischemia, that are essential players in the pathobiology of diabetic complications. The objective of the review is to highlight the possible role of NETosis in early diabetes-related vasculopathy beyond cardiovascular complications. Although the clinical significance of NETosis in diabetes beyond early atherosclerosis and cardiovascular complications is not still clear, there is limited data with respect to useful to use biological markers of NETosis aimed early stratification of the diabetics at risk of disease progression. Furthermore, several inductors of NETosis might be a target for novel pharmacological approaches to delay advance in diabetes and prevent diabetes-related vasculopathy.

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Extracellular Acidosis Is a Novel Danger Signal Alerting Innate Immunity via the NLRP3 Inflammasome

Cited by 287 publications

References 70 publications

Real-time analysis of composite magnetic nanoparticle disassembly in vascular cells and biomimetic media

Real-time analysis of composite magnetic nanoparticle disassembly in vascular cells and biomimetic media

Keratin mediates the recognition of apoptotic and necrotic cells through dendritic cell receptor DEC205/CD205

Is the neutrophil extracellular trap-driven microvascular inflammation essential for diabetes vasculopathy?

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