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Donation of kidneys after brain death

van Dullemen, Leon

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2017

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Citation for published version (APA):

van Dullemen, L. (2017). Donation of kidneys after brain death: Protective proteins, profiles, and treatment

strategies. Rijksuniversiteit Groningen.

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Heat shock proteins and

their protective role in

organ transplantation

Leon F.A. van Dullemen Bianca J.J.M. Brundel Henri G.D. Leuvenink

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ABBREVIATIONS

APC: Antigen Presenting Cell BD: Brain Death

CO: Carbon Monoxide

CMA: Chaperone Mediated Autophagy DAF: Decay-Accelerating Factor

DAMP: Damage-Associated Molecular Pattern DBD: Donation after Brain Death

DCD: Donation after Circulatory Death DNAJB1: Heat Shock Protein-40 GGA: Geranylgeranylacetone HO1: Heme Oxygenase-1 or HSP32 HSF-1: Heat Shock Factor-1 HSP: Heat Shock Protein

HSPA1A: Heat Shock Protein-70/-72 HSPB6: Heat Shock Protein-25/-27 HSPC1: Heat Shock Protein-90 HSPD1: Heat Shock Protein-60 ICP: Ischaemic Preconditioning IRI: Ischaemia Reperfusion Injury MHC: Major Histocompatibility Complex

LOX-1: Lectin-like Oxidized Low Density Lipoprotein Receptor-1 NEF: Nucleotide Exchange Factor

NFkB: Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells PAMP: Pathogen-Associated Molecular Pattern

PQC: Protein Quality Control System PRR: Pattern Recognition Receptor ROS: Reactive Oxygen Species TLR: Toll-Like Receptor

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ABSTRACT

Heat shock proteins (HSPs) are a conserved family of chaperones that become rapidly expressed upon cellular stress to protect the cell. During transplantation, donor organs are exposed to multiple types of injury varying from deceased brain death-related injury to hypoxia, ischaemia, reperfusion, and activation of the innate- and adaptive immune system. The upregulation of cytoprotective HSPs could preserve or increase graft quality and thereby improve transplantation outcome. In this review we consider in depth the intra- and extracellular working mechanism of heat shock proteins in organ transplantation and based on experimental studies we present evidence of organ protection in transplantation by heat shock protein upregulation.

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INTRODUCTION

Organ transplantation is inevitably linked with hypoxia and ischaemia during organ procurement, followed by reperfusion injury. Ischaemia/reperfusion injury (IRI) can be very detrimental for organ function and may negatively affects the short- and long-term graft survival. Compared to living donors, organs derived from deceased donors after brain death (DBD) or after circulatory death (DCD) are more susceptible to IRI.(1,2) Interestingly, although the DBD patient remains ventilated on the intensive care unit and a stable blood pressure is maintained, the organs procureded from these donors show an inflammatory response that could explain their high susceptibility to IRI and transplantation related graft injury. The inflammatory response in the DBD donor is not fully understood yet, but it originates from the cerebral injury and increased intracranial pressure, resulting in a strong sympathic response with severe vasoconstriction due to endogenous catecholamine release. After the onset of BD there is an increased systemic circulation of cytokines, chemokines, and adhesion molecules. (3-7) Eventually, BD will lead to decreased peripheral perfusion, generation of reactive oxygen species (ROS), leukocyte mobilisation and infiltration, and pro-inflammatory changes in the graft-to-be.(4,5,7-10) The pathological process of brain death with its systemic changes negatively affects the organ quality and is associated with a higher rate of primary non-function following transplantation as well as poorer short- and long-term outcomes when compared to optimal living donors.(1,11,12)

However, not only detrimental molecules are upregulated during BD and after IRI. At the same time an enhanced expression of cytoprotective proteins, in particular heat shock proteins, can be seen.(3,4,13-15) Heat shock protein-72 (HSP72 or HSPA1A), heat shock protein-25 (HSPB6 or HSP25), and heme oxygenase-1 (HO1 or HSP32) are proteins that are upregulated after stress. In tissue culture and animal models, elevated levels of HSPA1A, HSPB6, and HO-1 will protect or may repair damage thus preventing cell death.(16-18) Increased expression of HSPA1A and HO1 is able to provide protection against the detrimental effects of IRI in kidney(19-21), liver(22-24), and heart(25-27), and in the context of organ transplantation it is conceivable that enhancing the cellular contents of these proteins will benefit the donor organ quality. Furthermore, HSPs are especially interesting target molecules for transplantation since the expression can be boosted with non-toxic compounds, like GernalyGeranylAcetone (GGA).(28)

Although many articles in the literature focus on HSPs in transplantation or IRI, an overview how HSPs will exert their protective properties in transplantation is lacking. The aim of this review is to explain on a molecular level how HSPs protect against certain damage leading to reduced apoptosis and necrosis during transplantation-related injury in solid organ transplantation. The first part of this review will consider the mechanism how HSPs become upregulated and how these chaperones assist in the refolding or disposal of damaged proteins. Two common and extensively used pathways are highlighted in this review that dispose of proteins and protein aggregates and are facilitated by HSPS: the proteasome and autophagy pathway.

HSPs also exert extracellular functions that can trigger the innate- and adaptive immune system, which could be detrimental in allograft transplantation when provoking immune activation in

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the graft. Therefore, the second part of this review focuses on the mechanism how HSPs are released into the extracellular space and in what manner they may initiate innate- and adaptive immune responses. The latter part of this review will summarise the evidence of the protective effects of HSP upregulation in deceased donors, IRI, and organ transplantation.

HEAT SHOCK PROTEINS AND THEIR INTRACELLULAR FUNCTIONS

The viability of cells depends on synthesis and the functionality of its proteins. Proteins depend on their secondary and tertiary structure to fulfil their specific function. However, proteins are sensitive to extra- and intracellular stressors that influence their stability and conformation by exposing hydrophobic regions. Depending on the severity of injury and the conformational changes, proteins can no longer fulfil their specific function or are even no longer soluble and may form protein clusters in the cell, also known as protein aggregates. The accumulation of misfolded proteins and insoluble aggregates can be toxic to the cell and eventually lead to loss of function and induction of apoptosis. Therefore, it is important that the cell has a healthy homeostasis of protein synthesis, folding, assembly, and clearance, also referred to as proteostasis.(29) All cells are equipped with a protein quality control system (PQC) that assists in protein folding and protein degradation. The need for a correct functioning PQC is evident as cytoplasmic aggregates can affect membrane integrity, damage mitochondria, interfere with endoplasmic reticulum-associated degradation, and impair autophagy and vesicle transport. During transplantation a functioning PQC is important, since IRI is very potent in damaging proteins.(30)

Central to the PQC are HSPs.(31) HSPs were originally categorised into several families according to their molecular weight; HSP110, HSP90, HSP70, HSP60, HSP40, and small HSPs (e.g. HSP25). To date a new nomenclature has been proposed that is based on the function and similarity of domain functions; HSPH (HSP105=HSPH1), HSPC (HSP90=HSPC1), HSPA (HSP70=HSPA1A), HSPD (HSP60=HSPD1), DNAJ (HSP40=DNAJB1), and small HSPs (HSP27=HSPB1.(32) Several members of the HSP family are constitutively expressed proteins, but for some members their intracellular concentration can rapidly be enhanced upon cell stress, referred to as a heat shock response (HSR); hence the name of heat shock proteins (Figure 1). Most HSPs function as chaperones, taking part in the assembly, stabilisation, or folding of proteins. The protective mechanism of a heat shock relates to its preservation of cellular protein homeostasis and prevention of aggregation.

The heat shock response is regulated by interaction of the heat shock factor (HSF) transcription factors with the heat shock elements (HSE) in the promoter regions of the heat shock genes, resulting in enhanced HSP expression (Figure 2). There are four HSFs identified of which HSF1 is the main transcription factor in response to cell stress.(33,34) HSF1 is present in the cytoplasm as a monomeric molecule, unable to bind DNA or activate transcription. Upon proteotoxic stress, monomeric HSF1 becomes converted to a trimer that translocates to the nucleus and binds to the HSE.(33,35) Activation of HSF1 is further fine-tuned with posttranslational

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modifications such as phospohoryaltion and controlled by binding of HSPA1A and heat shock protein binding factor 1 (HSBP1) to the transactivation domain of HSF1.(33) HSPC1 (HSP90) and CCT are a negative regulator of this process (36) and active inhibition of HSPC1 enhances HSF1 related gene expression, a strategy often applied to increase cellular HSPA1A levels.(37) The most prominent HSPs of the cytosolic HSF1-dependent stress response are HSPB1 (HSP27), HSPB5 (alfaB crystalline), DNAJB1 (HSP40), HSPA1A (HSP70), HSPA6, and HSPA8 (HSC70).(38) Proteins central to the PQC system are chaperonins (HSP60, TCP-1 ring complex [TRiC]), the HSP90 (HSPC) family, the HSP70 (HSPA) family, the small HSPs (HSPB), and a set of co-chaperones, including the HSP40 (DNAJ) family and nucleotide exchange factor (NEF)

(Figure 2).(39,40) Heat shock protein 70 (HSPA1A) is involved in protein refolding and rapidly

upregulated upon stress. The HSPAs contain an N-terminal ATPase domain and a C-terminal peptide-binding domain,(41) and the function of HSPA1A is ATP-dependent and regulated by co-chaperones such as HSP40 (DNAJ) and nucleotide exchange factors (NEFs).(42) DNAJs recognise the unfolded or damaged protein and subsequently bind to the ATP-bound form of HSPA, after binding the ATP molecule is hydrolysed and DNAJ is released. Upon ATP-hydrolysis, HSPA undergoes a conformational change and binds the unfolded protein. The NEF binds to the ADP-bound HSPA and mediates the exchange of ADP for ATP, after which the target protein can be folded and released.(43,44)

The recognition of HSPs for misfolded proteins is through their affinity for hydrophobic regions, binding to these regions prevents the initiation of aggregate formation. In circumstances when aggregates are formed, HSPs can also prevent further nucleation of these aggregates. HSPA and HSPB family members are found to accumulate on the surface of aggregates, potentially reducing the toxic effects of these aggregates by preventing the trapping of other proteins to it.(45) Failure of damaged proteins to be refolded can lead to HSP-directed degradation through the proteasomal degradation machinery, or disposal of damaged proteins by exosomes, or autophagy (Figure 2).(46-50) How HSPA select substrates to be reused and refolded or disposed and degradated is not fully elucidated. DNAJs and NEFs contain ubiquitin interacting motifs or ubiquitin-like domains that could influence the protein folding machinery and direct it to degradation through the ubiquitin proteasome system (UPS).(40,51,52)

Ubiquitin proteasome system and HSPs

It is acknowledged that cytokines and metabolic dysfunction, as a consequence of e.g. DBD-related injury, IRI, or an activated immune system, can result in the production of ROS and damage proteins. When HSPs fail to refold a damaged protein, the protein can still be targeted for degradation by ubiquitylation (Figure 2). The UPS is an important pathway that can degrade these oxidative damaged proteins(53), and the PQC that efficiently degrades these proteins protects the cell from accumulating toxic aggregates.

Target protein ubiquitylation is a three-step enzymatic cascade; an E1 enzyme activates ubiquitin and transfers it onto an E2 ubiquitin-conjugating enzyme, subsequently, ubiquitin is shifted to a substrate-specific E3 ligases. The E3 ligases facilitate convalent binding of ubiquitin to the target protein, which targets it for degradation by the 26S-proteasome.(54) There are multiple

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genes encoded for E3 ligases, and one of such E3-ligase is C-terminus of Hsc70 Interacting Protein (CHIP or STUB1) which interacts mainly with DNAJ and HSPA chaperones.(55) In this way HSPs act as recognition factors of misfolded proteins and delivers those to the E3-ligase CHIP. Furthermore, HSPA1A and DNAJs are also essential to keep substrates soluble and make it accessible for the 26S-proteasome.(56,57) HSPA1A depletion has an inhibitory effect on the aggregation prevention of partially misfolded proteins that are otherwise soluble.

Interfering with the UPS system seems feasible in transplantation, although the protective mechanism seems counter intuitive. During the cold preservation of organs, intracellular proteins become massively ubiquitylated(58,59) resulting in an overloaded UPS. When inhibiting the UPS during organ preservation, the ubiquitin conjugate pool is preserved and the proteasome function is maintained at reperfusion(58). Two studies show that inhibition of the UPS during heart IRI is cytoprotective and prevents inflammation.(60,61) The protective effect of UPS inhibition in IRI is through the inhibition of NFkB. NFkB becomes activated after degradation of its inhibitor IkB, and UPS inhibitor administration prior to heart IRI prevents NFkB activation, cardiac dysfunction, and limits the infarct size.(60,61)

HSP-assisted autophagy

As mentioned above, besides targeting proteins for degradation, HSPs are also involved in protein degradation through autophagy on several levels. Autophagy is a pathway for the cell to degrade and recycle damaged organelles and proteins. The importance of autophagy in kidney transplantion has recently been reviewed by Pallet et al.(62) When autophagy is increased, the graft is more protected against transplant-related injury, while inhibition of autophagy enhances the cellular injury.(63)

During the process of autophagy a double membrane-vesicle is formed, containing the substrates targeted for degradation. The vesicle will fuse with a lysosome after which hydrolysis can take place. Soluble proteins can be chaperoned toward lysosomes by a pathway called chaperone-mediated autophagy (CMA).(64) The mediater of CMA is HSPA8 (HSC70), a constitutively expressed protein that recognises a specific peptide motif in the target protein. This allows it to bind the target protein and chaperone it to the lysosomes, where the protein will eventually be degraded. Besides CMA, HSPs can also target large growing aggregates for invagination by autophagosomes.(65) As described above, HSPs facilitate the polyubiquitination of damaged proteins, which allows recognition by ubiquitin-binding complexes leading to autophagy, also known as macroautophagy.(66) In addition, it is also believed that HSPs can re-route proteins to autophagosomes in the case that the proteasomal pathways are overloaded. (67,68)

Heme oxygenase

Another protective protein related with cell stress and extensively researched in IRI and transplantation is heme oxygenase-1 (HO1) or Heat shock protein-32 (HSP32). Heme oxygenase (HO) has three isoforms, of which HO1 is the inducible form that is upregulated in the deceased organ donor and proves to be protective in IRI.(13,21,69) HO1 is highly stress inducible but not

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by heat shock via HSF1. HO1 upregulation is mediated by inhibition of BACH1 and upregulation of NRF2.(70), A wide variety of stimuli can increase HO1 expression, possibly through oxidative stress. Stimuli that increase HO1 expression are e.g.; renal ischaemia, interleukins, TNF, IFN, TGF-beta, HGF, BMP-7, VEGF, heme, hemin, iron, angiotensin II, nitric oxide, carbon monoxide, gentamycin, cyclosporine, proteosomal inhibition, NGAL, and osmotic stress.(21,70,71) HO1 is often referred to as a HSP or stress protein although it lacks conventional HSP functions like refolding and stabilization of denatured proteins. HO1 is an enzyme that is involved in the breakdown of heme. Heme is a molecule constructed in many proteins like haemoglobin, mitochondrial cytochromes, NADPH oxidase, cyclo-oxygenase, and catalase. When cells become damaged, heme becomes released and inflicts cell injury.(72) In large quantities heme is very toxic and affects the plasma membrane, cytoskeleton, mitochondria, DNA, cytosolic enzymes, and induce renal injury.(73) Breakdown products of HO1-mediated heme metabolism are carbon monoxide (CO), free iron (Fe2+), and biliverdin that subsequently is converted to

bilirubin by the enzyme biliverdin reductase. The cytoprotective effects of HO1 are in part derived from the downstream products; 1. CO, 2. bile salts, and 3. through it’s effects on heme- and iron homeostasis.

Carbon monoxide (CO) is notorious for its toxic effects in large quantities, however, in low concentrations CO has cytoprotective, anti-apoptotic, vaso-relaxant and anti-inflammatory effects.(74,75) CO attenuates the expression of pro-inflammatory cytokines like TNF-alfa, and promotes the expression of anti-inflammatory cytokines like IL-10.(76) In animal experiments, exposure of rats to a CO-containing atmosphere protects the kidney from ischaemia reperfusion injury.(77) In this context, inhibition of HO1 also results in reduced glomerular filtration rate (GFR), renal blood flow (RBF) and these effects are reversible by administration of CO-releasing molecules.(78) Consistent with this, the protective effects of CO are not attenuated by inhibition of HO1 after administration of CO donor compounds.(79) Secondly, HO1 is responsible for the conversion of heme into biliverdin. While accumulation of bile salts are associated with cell injury, they exert anti-inflammatory and anti-oxidant properties also when present in low quantities.(80,81) Low elevated levels of bile salts are associated with lower NADPH activity, reduced ERK1/2 signalling, and reduced TNF-alfa induced endothelial activation.(82) The third downstream product of HO1 is iron (Fe2+). Iron is an oxidative reagent

that can induce the expression of ferritin and activate iron-transporters. HO1 upregulation is associated with an improved iron homeostasis and decreased free intracellular iron and iron induced cytotoxicity.(73,83-86) A potential fourth protective effect of HO1 is thought to be mediated by decreased expression of the pro-inflammatory protein: inducible nitric oxide synthase (iNOS).(87,88)

HSPS AND THEIR IMMUNOACTIVE PROPERTIES

Eukaryotic HSPs are considered intracellular proteins that are released upon cell necrosis and subsequently can initiating a range of pro-inflammatory processes in the extracellular environment (Figure 3).(89,90) It has been acknowledged that extracellular HSPs can function

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as inter-cellular signalling ligands and activate dendritic cells, monocytes, and other cells related to the innate- and adaptive immune system.(91-94) The exact receptor- and binding mechanism is not yet fully elucidated but potential receptors for HSPs include Toll-like receptors (TLRs)(95-97), scavenger receptors (SR)(98-100), CD40(101,102), and CD91(103). There is still no concensus if HSPs are able to initiate an immune response alone, or if the immune response is through HSP-bound peptides.(91) In skin transplantation the latter option seems to be the case, since HSP inhibition prevents allograft rejection.(104)

It has become apparent that HSPs have more than merely a passive role in activating the immunological processes upon cell decay, for instance, HSPs have also been detected in the serum of healthy individuals.(105-108) Apart from necrosis, the release of HSPs into the extracellular space is regulated through multiple pathways.

Extracellular release of HSPs

In the process of transplantation it is likely that the increase in extracellular HSPs is the result of ROS- and pro-inflammatory related cell damage and necrosis. The content of a cell is very high with HSPA1A, which can be up to 200µg of protein per 1g of necrotic tissue.(91) It is conceivable that irreversible injury to a cell, leading to necrosis, can easily enhance the extracellular HSP content measured in blood. An illustrative ischaemia reperfusion experiment in rats, where the blood flow to the middle lobe of the liver was blocked for 30 min, showed that after reperfusion there was a marked increase of HSPA1A in the plasma of 60.3ng/ml while the sham controls had levels of 0.02ng/ml.(109) A similar increase in HSPA1A was observed after treating animals with a heat shock of 42°C for 10 min, where plasma HSPA1A elevated from 0.04ng/ml to 99.4ng/ml.(110) Whereas, in the latter experiment one would only expect minimal if not any cell necrosis. However, it should be noted that HSPA1A expression is measured with ELISA in these studies that could bias the numbers due to aspecific binding for other HSPs.

Although two studies have found that HSPs secretion is an active and ATP-dependent process in multiple cell types (Figure 2), more evidence is needed.(111,112) One such excretion pathway is through secretory lysosomes. Extracellular HSP levels correlate with the appearance of the lysosomal marker, LAMP-1, on the cell surface, and HSP release can be inhibited with lysosomotropic agents.(112,113) The ABC-transporterappears to be a potential mechanism to translocate HSPs across the vesicle membrane, enriching the lysosome with these proteins. (112) Another way of excreting protein aggregates is by microvesicle formation and release via the exosomal pathway, or release through membrane blebbing.(47-50,114) It also appears that HSPs can become translocated across the plasma membrane, the exact mechanism is not understood but the mentioned ABC-transporter could be involved in this mechanism. The function of this HSP transport mechanism seems to be Mg2+-mediated, elevated levels

of extracellular Mg2+ inhibit Hsp70 secretion, while decreased Mg2+-levels enhances HSPA1A

secretion.(112) The in the end released extracellular HSPs are immonuactive and can initiate and activate the immune cascade by interacting with antigen presenting cells (APS).

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HSPs and the innate immune system

Molecular characteristics of prokaryote cell products are known as pathogen-associated molecular patterns (PAMPs) that can activate the immune response by interacting with specific receptors known as patterns recognition receptors (PRR), which triggers the innate immunity. One of those PRRs is the family of Toll-like receptors (TLRs) that can activate pro-inflammatory signalling. Similar to PAMPs, the release of intracellular components will also trigger the innate immunity in a sterile manner by molecules referred to as damage-associated molecular patterns (DAMPs).(115)

When cells die by apoptosis, their intracellular content remains enveloped with an external membrane, preventing extracellular release that could trigger inflammation. The apoptotic cells express ‘eat me’ signals on the surface, which induces phagocytosis by macrophages. The roll of HSPs in phagocytosis is unclear, but scavenger receptors associated with endothelial cells (SREC-I)(99,100) and CD91 posses sequence similarities to HSPs, suggesting a role in the process of phagocytosis.(98) Upon stress, cells are able of expressing HSPs on their extracellular plasma membrane that has shown to activate macrophages, and upregulation of HSPA1A (HSP72) in macrophages increases their phagocytotic capacity.(116-118) Furthermore, increased levels of extracellular HSPB1 (HSP27) can trigger the NF-kB pathway in macrophages. (119) Interaction of HSPA1A with CD40 also activates macrophages and enhances interleukin secretion (Figure 3).(120) Consistent with this, extracellular HSPD1 (HSP60) could increase the influx of macrophages since it induces the expression of adhesion molecules E-selectin, intracellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1. In addition, HSPD1 also increases the secretion of IL-6 from several cell types and macrophages.(121,122)

Many reports suggest that Toll-like receptors (TLRs) can become activated by HSPs, however, there is much controversy around this topic. HSPs have been produced in bacteria and lipopolysacharide (LPS) derived from those bacteria can become bound to the HSP. LPS triggers NF-kB and MAP-kinase signalling via the activation of TLR4 and therefore could be a biased activation mechanism of TLRs in in vitro studies with purified HSPs. The mechanism how HSPs trigger TLRs is not fully understood but it is likely to be through the interaction of the chaperoned protein. However, several studies have shown that extracellular HSPA1A function in a LPS independent manner and can elicit the production of cytokines, even after adding a LPS inhibitor.(89,90)

The extracellular function of HSPA1A as a DAMP seems to be mediated through TLR2 and -4, enhancing the expression of NF-kB, ICAM-1, MCP-1, IL-6, -8, TNF-alfa, and IL-1beta.(123-128) Also, HSPA1A and its bound peptides isolated from tumour-dendritic cell can induce an anti-tumour immunity reaction, while knock-out of the TLR2 and -4 genes decreases the inflammatory response of an HSPA1A vaccine.(99) The exact mechanism is not known but some studies show that HSPD1 and HSPA activate TLR2 and -4 pathways through SREC-1, LOX-1, and CD14 receptors.(90,95,99,121)

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Besides the TRL-system, HSPs might also interact with the complement system, a major arm of the innate immune system. The inhibition of extracellular HSPA1A in tumour cells also has an inhibitory effect on the expression of complement components C3, C5, and C9.(129) The opposite appears for overexpression of HO1, which enhances the expression of decay-accelerating factor (DAF) through increased bilirubin levels, and improves protection against C3-deposition and complement-mediated cell lysis.(130)

HSPs and the adaptive immune system

The adaptive immune system can be triggered by major histocompatibility complex (MHC) class I or –II receptors. MHC-I molecules are present on all nucleus-containing cells and activate CD8+ T-lymphocytes, while MHC-II molecules are only present on antigen-presenting cells (APCs) and activate CD4+ T-lymphocytes. Extracellular antigens are internalized into an endosome or phagosome and those peptides are presented on MHC-II molecules, activating CD4+ T-lymphocytes upon appropriate co-stimulation. A second pathway to present antigens involves translocation of the antigen into the cytosol and degradation via the ubiquitin-proteasome pathway where it can subsequently be presented by MHC-I molecules to CD8+ T-lymphocytes.(131) This process is called cross-presentation and is important for an effective host defence against viral infections and malignancies.(132) The molecule CD91 present on APCs interacts with HSP GP96 and becomes internalized upon interaction (Figure 3).(103) The chaperone with the bound peptide either becomes degraded and loaded to a MHC class-I or –II molecule, or transferred to the cytosol, degraded by a proteasome and subsequently presented on MHC class-I molecules.(133-136) Also, HSPC1 associates with proteins destined for proteosomal degradation and HSPC1 inhibition affects protein loading on MHC-I molecules. (137) Furthermore, HSPC1 also plays a role in chaperoned antigen presentation on MHC-II molecules, and increased levels of extracellular HSPC1 enhances cross presentation of these antigens.(137,138) Downregulation of HSF1 and HSPC1 seems to decrease antigen presentation of APCs on both MHC-I and -II molecules, and also affect T-lymphocyte activation via MHC-I molecules on target cells.(139-141) Therefore, it seems that chaperoning of proteins and peptides is important for effective cross-presentation and activation of the adaptive immune system. Furthermore, HSPA1A can also capture antigenic substrates that are released, and after binding to receptors on APCs, they subsequently trigger CD8+ T-lymphocytes by antigen presentation on MHC-I molecules.(93,99,142)

Another function of extracellular HSPs is activation of APCs after interacting with CD40. (120,124,143) It appears that binding of HSPA1A to APCs generates a pro-inflammatory response through the activation of various immune processes, such as cytokine production (IL1b, TNF-alfa, and IL6,), co-stimulatory molecule expression (MHC class II and CD86), and nitric oxide (NO) release. Another candidate receptor for HSPs is the scavenger receptor (SR) family, which are expressed on the surface of APCs. It has been shown that HSPA1A can interact with at least three of those members, including SREC-1, FEEL-1/CLEVER-1, and LOX1.(100,144) The latter, LOX-1, is involved in the homing and adhesion of APCs to endothelial cells, mediating cell influx that could initiate an immune response.

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Although HSPs have not been extensively investigated in the context of transplantation and immune activation, it is probable that HSP-mediated activation of the innate- or adaptive immune system will be detrimental for the graft. However, as outlined in the next paragraph, it appears that for some HSP-members upregulation results in a better functioning graft post IRI, also after allogeneic transplantation. This was illustrated in a mouse heart transplantation model where enhanced expression of HSPB1 resulted in lower rates of acute graft rejection and apoptosis.(145)

PROTECTIVE EFFECTS OF HEAT SHOCK PROTEINS IN TRANSPLANTATION

The precise protective mechanism of HSPs in inflammation- and ischaemia reperfusion related injury is not very well understood, but may be mediated through their biological function as molecular chaperones. HSPs became of interest in the setting of transplantation since they first appeared to be protective in ischaemia reperfusion injury in hearts.(146) Upregulation of HSPs also appears to be protective for IRI and DBD-associated injury in in vivo animal experiments of several organs, including the kidney(19,20,147,148), liver (23,149,150), heart (25,26,151,152), lung (153), and small intestine (154) (Table 1). Upregulation of HSPA1A protects cells from TNF-alfa and monocyte induced inflammation and cytotoxicity.(155-157) In a sepsis model HSPA1A upregulation is associated with protection of the endovasculature and the lung.(158-161) Also, cold shock, a common injury mechanism in the preservation of organs, is associated with decreased expression of HSPA1A, HSPB1, and HSPC1. Enhancing the expression of these depleted HSPs by heat shock provides protection against cold storage and rewarming injury. (162) Similar protective properties against IRI have also been observed after enhancing HO1 expression in kidney and liver.(21,163-165) Pre-treatment of the donor by upregulating HO1 appears to be a useful strategy for improving the graft quality in a rat transplantation model. Cobalt-protophyrin administration is a commonly used method to enhance HO-1 expression, although it should be noted that this compound is not solely specific for HO-1. A single dosis of cobalt-protoporphyrin improved the kidney graft in an allogeneic- and also in a brain dead transplant model.(166,167) HO1 upregulation improved the survival rate, ameliorated the amount of proteinuria, and inhibited NFkB activation and cytokine expression. Just this year Thomas et al. showed very promising results on the possibility to enhance HO1 expression in deceased human donor kidneys.(168) The clinical importance of HO1 is emphasized by the observation that donors with a polymorphism in the HO1 gene, resulting in higher HO1 expression levels, have a superior graft function and survival.(169,170) In addition, older age is associated with inferior transplantation outcomes. This could partly be mediated via HSP expression since both HO1 and HSPA1A expression levels appear to be age-associated. (170-172) Also with increasing age the PQC system fails to prevent and eliminate misfolded proteins, lysosomal function decreases, and autophagy becomes more impaired.(173-176) In a rat IRI model, older rats have an impaired ability to enhance HSPA1A expression and are more susceptible for ischaemic injury.(172) Consistent with this data, the ability of HSF1 to bind to the HSP-promoter regions also diminishes with ageing.(177) A possible contributing cause could be that SIRT1, a molecule that affect HSF1 acetylation and expression, shows an age- dependent decline.(178)

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HSPs are especially interesting target molecules to improve graft quality as their cellular content can easily and rapidly become upregulated with several compounds (Table 2). GGA is a very promising HSP boosting compound.(179) In contrast to most compounds, GGA is non-toxic and capable to boost HSP expression in a wide variety of tissues including stomach, intestine, kidney, liver, heart, lung, and nerve tissue.(19,23,180-183) GGA boost HSP expression via a delayed release of HSF1 from the promoter region, and is more potent under stressed conditions.(180,184) Importantly, GGA has been on the market in Japan for over 30 years as a stomach antiulcer drug and its protective properties have been shown in several in vivo experiments (Table 1). GGA pre-treatment greatly increased the survival rate in a syngeneic rat liver transplantation model.(23) In this experiment the survival of vehicle-treated rats was 0% at day two, whereas the survival in GGA pre-treated rats was 100% after seven days. The protective effects of GGA were associated with increased expression of HSPA1A and HSPC1. (23) GGA also exerts protective effects in vivo against IRI in heart (152,185), and drug induced damage in rat lung (186). In a kidney IRI model, pre-treatment of rats with GGA improved the survival rate and protected the kidney against apoptosis and infiltration of monocytes. This effect was abolished after administration of quercetin, which is an HSPA1A inhibitor (19). Consistent with this, the protective effects of GGA were abrogated in HSPA1A knockout mice that were subjected to kidney IRI.(20)

Although protective effects of GGA have been documented in IRI-stress, an important disadvantage of GGA is its high log P value (approximately 9), therefore a relatively high dosage is required for therapeutic effects and the possibility for intravenous administration is limited to low dosages. Synthesized derivates of GGA, with improved pharmacokinetic properties have been constructed and show promising HSP-inducing properties in heart tissue. (187) Exploiting these new compounds could be a valuable asset in the treatment of organ donors prior to transplantation, or potentially even the donor organ itself in a closed circuit machine perfusion set-up.

Ischaemic preconditioning (IPC) is an approach to protect organs from IRI by clamping the organs artery (local IPC), or another organ or limb (remote IPC). IPC has been reported to be protective in rodent models of heart, kidney, and liver transplantation.(14,188-191) Promesing effects were seen on the glomerular filtration rate in transplanted kidneys of pigs treated with remote IPC.(192) However, to date these protective effects could not be reproduced in a porcine IPC or human remote IPC study.(193-196) The exact protective mechanism of IPC is not fully elucidated, but it is likely that HSPs have a part in the protective mechanism. Intermittent clamping has a more potent HSP upregulatory effect compared to continues preconditioned clamping.(14) Also, preconditioning was more potent in enhancing HO1 expression and autophagy in IRI kidneys.(191) Whether HSPs are the protective mediator in IPC is not fully elucidated so far, but in a rat model for IRI it was shown that the capacity of kidneys to enhance HSP expression upon remote IPC correlated with better recovery.(197) Therefore, it is conceivable that healthy tissue that is capable of enhancing HSP expression may also be more protected from transplant related injury such as IRI.

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CONCLUSION

The heat shock response represents a mechanism of cellular protection after injury by chaperoning damaged proteins. Activation of this pathway occurs after a variety of stimuli resulting in rapid transcription of several different kinds of HSPs. The most studied HSP in transplantation is HSPA1A and expression of this protein is enhanced after injury in all transplantable organs. Three potential mechanisms explain the protective function of HSPA1A: 1. preservation of protein structure and configuration, 2. attenuation of cytokine-induced inflammation, and 3. reduced cell death as a consequence of preserved protein structures. Intracellular located HSPs have cytoprotective properties, while extracellular HSPs can attenuate the immune system. The mechanism of HSP-release is partially by secretion and, in transplantation probably predominantly by necrosis. Despite the immune attenuating properties of extracellular HSPs, upregulation of intracellular HSPs prior to transplantation show promising results on ameliorating tissue injury and exploiting these molecules could be an elegant way to improving future transplantation outcomes. Further work has to be performed to determine dosage, timing, and frequency of drug administration to optimally enhance HSP expression and improve organ quality.

ACKNOWLEDGEMENTS

The authors would like to thank Harrie Kampinga and Felix Poppelaars for critically reviewing this article.

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TABLES AND FIGURES

Table 1. HSP-associated protective effects in transplantation-related injury

Family Protein Organ Injury Organism References

HSPA HSPA1A (HSP70) Heart IRI/TX Rat/Mouse/Rabbit (25,26,152,184,198-201)

Lung IRI Rat/Pig (202,203)

Kidney IRI Rat/Mouse (19,20,147,148,204-206)

Liver IRI Rat/Mouse (22,23,149,150,190,207-209)

Intestine IRI Rat (154,210,211)

HSPB HSPB1 (HSP25/

HSP27) Heart IRI/TX Rat/Mouse/Dog (145,212-214)

Kidney IRI Mouse (215)

Liver IRI Mouse (216)

HSPB6 (HSP20) Heart IRI Rat (217)

DNAJ (HSP40) -

-HSPD1 (HSP60) -

-HSPC HSPC1 (HSP90) Heart IRI Pig (218)

Kidney IRI Rat (15,148)

Liver IRI Rat (149)

HO HO1 (HSP32) Kidney BD/IRI/TX Rat (21,166,167,219,220)

Liver BD/IRI Rat (24,221-224)

Heart IRI/TX Rat (27,225-227)

*IRI: ischaemia reperfusion injury, BD: brain death, TX: allogeneic transplant model

Table 2. HSP boosting compounds

Compound Protein References

Geranylgeranylacetone (GGA) HSP1-inducable HSPs: HSPA1A

(HSP70) (20,23,152,180,183,184,186,187,228) HSPA8 (HSC70) (180) HSPB1 (HSP25/27) (213,229,230) HSPC1 (HSP90) (23,180,183) HSPD1 (HSP60) (180) HSPH1 (HSP105) (183) Dexametason HSF1-inducable HSPs (231) Bimoclomol HSF-1inducable HSPs (232,233) Glutamine HSPA1A (HSP70) (160,204,234,235) HSPB6 (HSP20) (160)

17-DMAG (HSP90 inhibitor) HSPA1A (HSP70) (159,236)

Cobaltprotoporfyrin HO1 (HSP32) (21,24,166,167,237)

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Figure 1. Time-dependent HSPA1A protein expression. Human kidney (HK-2) cells were treated in vitro

with a heat shock of 42°C for 30 min and harvested at different time points. Heat shock protein-70 (HSPA1A) protein levels were measured with Western blot using a mouse monoclonal antibody (Spa-810, Enzolifesciences, Farmingdale, USA), the fold induction was corrected for protein levels of the housekeeping gene ß-actin.

Figure 2. Heat shock protein mediated substrate folding or disposal. HSPs (e.g. HSPA1A, HSPA8 HSPB1,

HSPC1, HSPD1, DNAJ) and nucleotide exchange factors (NEF) interact and assist in the recognition and refolding of denatured proteins. If refolding fails, the substrate can become targeted for degradation after tagging with a poly-ubiquitin tail by E3-ligase (e.g. CHIP)(55,239) or in lysosomes with a pathway known as chaperone mediated autophagy(46,64). Once misfolded proteins organise into insoluble aggregates, the only elimination options are disposal outside of the cell or through macroautophagy. HSPA1A and HSPB1 bind to protein aggregates to maintain solubility(45) and in this manner mediate macroautophagy(65), disposal via membrane blebbing(50), or excretion via the exosomal pathway(49).

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Figure 3. Heat shock protein mediated inflammation. HSPs can mediate an inflammatory response

upon release in the extracellular space by interacting with antigen presenting cells (APC). HSP release is possible through; 1. membrane blebbing(50) and lysis of these vesicles in the extracellular space, 2. lysosomal exocytosis(113) after lysosomal translocation by an ABC-transporter(240), 3. cell membrane translocation via an unknown mechanism, 4. exosomal pathway, or 5. necrosis related. Extracellular HSP-antigen complexes can interact with CD91(103) and activate CD8+ and CD4+ lymphocytes via majorhistocompatibility complex (MHC) class I or –II molecules (133-138). The HSP-peptide complex can also elicit a pro-inflammatory response upon interacting with Toll-like receptor (TLR)-2 and -4(128), CD40(120,143), and Scavenger receptors (SRs)(100), resulting in transcription of NFkB, adhesion molecules, and cytokine release(127).

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