The Inflammatory Response to Ischemic Acute Renal Injury

Acute ischemia reperfusion injury (IRI) is a major cause of acute kidney injury (AKI). A major conceptual insight is that the total amount of renal injury is the result of not only the initial ischemic insult, by the ensuing responses. This simple insight has profound clinical implications: it suggests that therapy after the initial insult has already occurred may ameliorate the course of AKI. Some of these responses are maladaptive. Examples include inappropriate intrarenal hemodynamics, altered mitochondrial and other metabolic functions, endothelial dysfunction, and tubular obstruction and back-leak. Other responses are reparative. Examples include the production of growth factors such as Wnt7.

In addition to the above, IRI elicits an inflammatory response. Some components of this inflammatory response exacerbate injury, other components mediate repair. In either case, inflammation is a major determinant of the ultimate outcome of ischemic AKI. A complete understanding of the inflammatory response to IRI—the composition and functions of the leukocytes, the stimuli that elicit inflammation, and the regulation of inflammation—remain a fundamental unsolved problem in renal disease. The goal of this chapter to provide a perspective on our rapidly growing insights into the inflammatory response to IRI.


Acute ischemia reperfusion injury (IRI) is a major cause of acute kidney injury (AKI). A major conceptual insight is that the total amount of renal injury is the result of not only the initial ischemic insult, by the ensuing responses. This simple insight has profound clinical implications: it suggests that therapy after the initial insult has already occurred may ameliorate the course of AKI (see Figure 88.1 ). Some of these responses are maladaptive. Examples include inappropriate intrarenal hemodynamics, altered mitochondrial and other metabolic functions, endothelial dysfunction, and tubular obstruction and back-leak. Other responses are reparative. Examples include the production of growth factors such as Wnt7.

Figure 88.1

Injury after ischemic AKI is the sum result of the initial insult, subsequent maladaptive, and adaptive responses. Original figure.

In addition to the above, IRI elicits an inflammatory response. Some components of this inflammatory response exacerbate injury, other components mediate repair. In either case, inflammation is a major determinant of the ultimate outcome of ischemic AKI. A complete understanding of the inflammatory response to IRI—the composition and functions of the leukocytes, the stimuli that elicit inflammation, and the regulation of inflammation—remain a fundamental unsolved problem in renal disease. The goal of this chapter to provide a perspective on our rapidly growing insights into the inflammatory response to IRI.

In addition to its importance for injury of the native kidney, the inflammatory response to IRI is important for transplantation. Ischemic injury to the allograft inevitably accompanies organ harvesting, the cold storage, and the warm ischemia during the surgical creation of the vascular anastomoses between allograft and recipient. In addition, for brain dead donors, the donor kidneys are damaged by the hemodynamic instability resulting from the trauma that causes brain death. The leukocytes recruited to the allograft by ischemia exacerbate rejection. This is predicted by the “danger” theory of immunology where injury elicits inflammation, the leukocytes detect non-self at the site of injury (infectious pathogens or the allograft), and then develop an immune response against the non-self. The relation of this “injury response” to rejection has previously been reviewed.

An inflammatory response is also elicited by chronic injuries in common human diseases such as progressive renal failure from diabetes and hypertension. Understanding the inflammatory response to the “single hit” model of acute ischemia may aid our understanding of the more complicated chronic diseases. The goal of this chapter is to review our current understanding of this rapidly evolving field. Although complement and gene activation by hypoxia/reactive oxygen species are important, our focus will be on the nature of the inflammation and its regulation by injured and dying cells.

Most studies of the inflammatory response to renal ischemia have involved rodents. The potential difficulties in extrapolating such studies to the clinical setting have been discussed previously. Although inflammation is not a prominent feature of human ischemic acute renal failure, leukocytes are present. The susceptibility of patients to acute renal failure may correlate with polymorphisms of pro- and anti- inflammatory genes; and this further supports a role of inflammation in the pathogenesis of human disease. Biopsy studies during ischemic acute renal failure of native human kidneys are limited, but post-anastomosis biopsies of renal allografts are increasingly common. Most such biopsies indicate inflammation, particularly in deceased, compared to living, donors. Furthermore, intraoperative biopsies have also indicated expression of pro-inflammatory genes. Such inflammation may be a response to ischemic injury to the allograft due to the hypotension associated with the trauma that caused brain death, due to the cold storage, and due to the warm ischemia during creation of the vascular anastomoses. In addition, inflammation in the cadaver kidneys was also caused by neurohormonal effects of brain death. Inflammation during these intraoperative biopsies are not due to rejection because there is no time for immune recognition of the transplant. Furthermore, biopsies of kidneys between identical twins, where there is no allo-recognition, also shows inflammation that must be due to ischemic injury occurring during the transplant process.

Some argued that injury and damage to kidney is not the major contributor to most cases of human ischemic AKI. Instead the major factor is abnormal renal microvascular function and use of oxygen. Indeed, in those rare cases where the kidney is biopsied, the morphologic injury by conventional staining techniques are minimal. However, the longterm maladaptive effects of ischemic AKI suggests that injury does occur and the kidney never completely recovers from this injury. Indeed, recurrent episodes of ischemic AKI may be a major contributor to the current epidemic of CKD.

The medullary thick ascending limb and the S3 straight proximal tubule in the outer medulla are the tubules most vulnerable to ischemic injury in both rodents and humans. This is the area with the greatest inflammation. Although the outer medulla is the injured earliest and after the least ischemia, longer periods of ischemia result in the injury of the cortex also. Because different structures in the kidney may be injured depending on the intensity of ischemia, and because these structures produce different cytokines, chemokines, and other regulatory molecules in response to IRI, renal IRI may be a family of diseases rather than a single entity. Thus, the length of ischemia time, or the temporature of ischemia may modify the inflammatory response to IRI.

The inflammatory response to acute ischemia of the heart, and brain have been more intensively studied than ischemic acute renal failure because of the greater clinical incidence of coronary artery disease and stroke. Where renal studies are not available, we will review studies from these and other non-renal organs. Although the general principles may be the same in these various organs, the particular mechanisms of the inflammatory response to ischemic injury may be different in different organs. For example, blocking the pro-inflammatory cytokine interleukin 1α and β ameliorates ischemic injury of the rodent brain and heart, but has no effect on ischemic acute renal failure.

Leukocytes in Injured, Ischemic Tissues: Friend, and Foe.

Over a decade ago, anti-inflammatory agents were shown to ameliorate ischemic acute renal failure. These studies demonstrated the maladaptive effects of the inflammatory response to injury. Recent studies elucidate greater detail about which leukocytes are involved and how they regulate renal IRI.

Mononuclear phagocytes—monocytes, macrophages and dendritic cells : The relationship of the various members of the mononuclear phagocyte family—monoctye, macrophages, and dendritics, and there various subsets—is complex. Various mononuclear phagocytes participate in ischemic AKI. Some exacerbate injury. Others facilitate repair.

These leukocytes exacerbate the early phases of ischemic injury. Macrophages appear within hours after ischemic injury in both mice and rats; these macrophages are located adjacent to the vasa rectae of the outer medulla. This is the region of the rodent kidney that is most vulnerable to ischemic injury, and where there is endothelial injury and expression of both B7 and adhesion molecules.

Elimination of this early macrophage infiltrate prevented the increased interleukin 6 that occurs after renal ischemia. The former exacerbate ischemic renal injury because its elimination by transgenic knockout, or anti-interleukin-6 antibodies ameliorates renal injury. In situ hybridization shows that interleukin 6 is produced by macrophages in the ischemic kidneys; the construction of bone marrow chimeras where renal parenchymal cells or macrophages have their IL6 gene knocked out showed that the greatest injury occurred when macrophages were capable of making interleukin 6. Macrophages are also capable of producing a number of other molecules that might exacerbate ischemic acute renal failure. However, as discussed below, what cytokines are produced by which renal cells, and which cytokines have harmful versus helpful effects remain to be clearly delineated.

In these studies, there was an early infiltration of macrophages in the absence of neutrophils. This sequence of macrophages then neutrophils contradicts the classical paradigm which proposes that neutrophils infiltrate first, and produce molecules that recruit monocytes subsequently. However, recent data indicate that monocytes can infiltrate tissues early and, in some cases, in the absence of neutrophils. In the lung and liver, macrophage inflammation may precede neutrophilic inflammation. This may also occur in ischemic acute renal failure. Furthermore, the nature of renal cell death during ischemic AKI may regulate the type of inflammation. Apoptosis generally recruit macrophages, but necrosis recruits neutrophils. We discuss the various types of cell death and their effects in inflammation later in this chapter.

In addition to this early infiltrate, there is also a late infiltrate of macrophages and related dendritic cells during the first weeks after acute ischemic injury. Large numbers of these leukocytes are still present after the recovery of glomerular filtration has already occurred. The contribution of these leukocytes to renal injury and repair is not known. On the one hand, they may contribute to chronic injury. On the other hand, some macrophage subpopulations participate in tissue repair, perhaps through the secretion of growth factors such as Wnt7b or anti-inflammatory cytokines such as interleukin 10. These macrophages have many attributes of “M2” macrophages present late after infections.

Macrophage infiltration into the outer medulla is regulated by endothelia. Endothelia are the border between the vasculature and the renal interstitium. Thus, the quantity and composition of leukocyte traffic from blood into the renal interstitial spaces is regulated by proinflammatory genes expressed by endothelia. Ischemic endothelia in the outer medulla do increase their expression of pro-inflammatory ICAM-1 (CD54) and B7. 1 (CD80). In addition, endothelial expression of P-selectin (CD62P) and VCAM-1 (CD106) also contribute to the inflammatory response to renal ischemia, but the precise anatomical location is not known. Inactivation of ICAM-1 and selectins via antibodies, antisense oligonucleotides, or transgenic knockout ameliorates inflammation and injury after acute ischemia.

Furthermore, macrophage infiltration into the ischemic kidney is regulated by MCP 1, a chemokine that attracts macrophages are expressed by the ischemic kidneys. Transgenic knockout of the receptor for MCP 1 (CCR2) or administration of a truncated, inhibitory form of MCP 1 both ameliorate ischemic injury and inflammation.

In addition, macrophages may be recruited by molecules released by necrotic or apoptotic cells. This will be discussed in later sections of this chapter. Finally, blocking B7 on ischemic endothelia decreases macrophage infiltration and ischemic renal injury. CD28, the ligand for B7, is not known to be expressed by macrophages, but is expressed by T cells. This suggests a role for T cells in ischemic acute renal failure (see below).

Neutrophils : In contrast to the early infiltration of macrophages, some studies report that there is a later infiltrate of neutrophils. The role of these neutrophils is not clear. Early reports suggested that elimination of these neutrophils with antibodies ameliorated ischemic injury. But this may have reflected the use of polyclonal antibodies that actually recognized both neutrophils and macrophages. Recent data using monoclonal antibodies for neutrophils are controversial. Some, but not others, find that deleting neutrophils ameliorated ischemic injury. One difficulty in these studies is the use of the monoclonal antibody for Ly6C/G (Gr1). Although Ly6C/G is highly expressed on neutrophils, it is also expressed, albeit weakly, on some subsets of monocyte/ macrophages.

Renal parenchymal cells produce the neutrophil chemokines KC and MIP 2, the murine analogs for human interleukin 8, as well G-CSF that would stimulate neutrophil production by the bone marrow. In one study, antibody to the neutrophil chemokines KC and MIP 2 decreased neutrophilic infiltration and also ameliorated ischemic injury. However, antibody to the receptor for these chemokines CXCR2 unexpectedly exacerbated injury. These results need to be reconciled. One possibility is that these chemokines have both maladaptive and adaptive functions; in addition to regulating neutrophilic inflammation, KC and MIP 2 may also regulate the differentiation of renal tubular cells during the repair process after injury.

Those advocating a role for neutrophils point out that, in addition to releasing toxic molecules that might injure the kidney, neutrophils are now known to produce cytokines, chemokines, and other regulatory molecules. By producing these molecules, neutrophils may regulate any subsequent inflammation and repair. Those, who find no role for neutrophils in renal injury, might argue that the presence of neutrophils in tissue does not necessary indicate that these neutrophils are activated. Thus, extopic gene expression of the neutrophil chemokine KC results in a neutrophilic infiltrate but no tissue damage, presumably because the neutrophils are not activated to produce toxic molecules. This neutrophil infiltration may be regulated by NK T cells.

Lymphocytes : Small numbers of T cells are found in kidneys after renal ischemia. The role of these T cells is not understood. On the one hand, elimination of T cells via the foxn1 mutation (nude mice) ameliorated injury. FTY720, an immunosuppressive drug that traps lymphocytes in lymph nodes, inhibits ischemic acute renal injury. But, on the other hand, elimination of all classical T cells via mutation of the TCRα chain or via mutation of the rag gene (scid mice) did not inhibit. There is further controversy when elimination of specific subsets of T cells was examined. On the one hand, eliminating CD4 T cells with monoclonal antibodies did not ameliorate injury, but elimination with transgenic knockout did. Similar controversy surrounds the role of CD8 T cells. On the one hand, transgenic knockout of CD8 did not ameliorate ischemic injury; however, anti-CD8 antibodies used in combination with anti-CD4 antibodies did. B-lymphocytes may also contribute to ischemic AKI. This is discussed further in the section on complement and “natural” antibodies.

The role of lymphocytes in ischemic injury is further complicated by observations suggesting that T cells ameliorate injury in some models. These studies fall into three groups: those involving CD4 T cells, those involving interferon gamma, and those involving “unconventional” γδ T cells.

Some CD4 T cells may ameliorate injury. CD4 knockout results in decreased HGF production and increased tubular apoptosis after ureteral obstruction. Nude mice with no classical T cells have increased injury after optic nerve injury, and injection of such T cells improves repair. CD4 T cells play a dual role of exacerbating and inhibiting inflammation after ischemic hepatic injury.

Interferon gamma may play a dual function. Interferon gamma is a cytokine associated with ischemic injury, and produced in quantity by T cells. Interferon gamma exacerbates ischemic acute renal failure in some models. However, there are interferon gamma dependent pathways of tissue repair. Whether or not there are such pathways in the kidney is not known.

Recent data suggest that unconventional T cells recognize injured tissues. Thus, some T cells with γδ T cell receptors recognized stressed epithelia and release keratinocyte growth factors that facilitate repair. Whether or not such T cells are present in the ischemic kidney is not known. NK T cells also participate in ischemic AKI and some NKT cell regulate inflammation during AKI.

The Proinflammatory Effects of Injury—Damps, Sterile Inflammation, and the “Danger/ Damage” Hypothesis

Although the above shows that the inflammatory response to ischemia may an important determinant of the extent of injury and repair, how ischemic injury is translated into inflammation is a major outstanding question. Approaches to addressing this question are reviewed in the remainder of this chapter. Several concepts and terms need to be defined before beginning our discussion. A major recent concept is that injury itself is proinflammatory. The proinflammatory signals are generated in several ways. Molecules, normally residing within cells, elicit inflammation when they are released into the extracellular space or are expressed on cell surfaces. In addition, enzymes released by injured cells or leukocytes convert extracellular matrix molecules into proinflammatory signals. Finally, intracellular stress may generate proinflammatory signals. Altogether these proinflammatory molecules have been called “danger (or damage)-associated molecular pattern” molecules (DAMPS) or Alarmins. This inflammatory response to injury has been called the “danger” response or “sterile” inflammation to differentiate it from the inflammatory response to infections.

The biology of DAMPS, their receptors, and their regulation of injury, of the inflammatory response to injury, and of repair remain to be completely elucidated. The biology is complex because the receptors are promiscuous and interact with numerous DAMPS, because each DAMP interacts with multiple receptors, because DAMPS interact with each other, and because the cellular response to a DAMP is unique to the cell and its microenvironment. We review our current understanding of this rapidly evolving field with the humble realization that this understanding will certainly change in the future.

TLR4 and HMGB1

During ischemic AKI, the best characterized receptor for DAMPS is TLR4. TLR4 is best known as the receptor for endotoxin produced by gram negative bacteria, and mediates the inflammatory response against these bacteria. It is one member of a family of “pattern recognition receptors” that recognize molecules produced by pathogens. In addition to endotoxin, these molecules include viral DNA, viral RNA, and sugar molecules unique to yeast. The TLR’s are present on most leukocytes of the “innate” immune response—macrophages and neutrophils. They are critical for the immediate inflammatory response against infections.

A major discovery was the insight that TLR4 not only recognizes endotoxin, but also recognizes DAMPS. These molecules are called “endogenous” because they are produced by mammalian cells and to differentiate them from endotoxin, the “exogenous” TLR4 ligand that is produced by gram negative bacteria.

Striking confirmation for the importance of TLR4 in ischemic disease were experiments comparing inflammation and injury in wildtype mice versus TLR4 deficient mutant mice after ischemia to the heart, liver, lung, and kidney. In all of these studies, mutant mice with non-functional TLR4 are protected from ischemic injury. Furthermore, human mutations that inactivate TLR4 ameliorate post-transplant ischemic AKI.

HMGB1 is released from injured cells and is the best documented DAMP ligand for TLR4 during ischemic AKI. The HMGB1-TLR4 interaction is one of the few DAMP-TLR4 interactions that have been confirmed by biophysical studies. Furthermore, HMGB1 has a proven role in ischemic AKI. Its expression increases in both murine ischemic AKI, and biopsies of human renal transplant grafts that had ischemic AKI during the transplant process. Antibodies that inactivate HMGB1 ameliorate murine ischemic AKI. Altogether this data show HMGB1 has maladaptive functions during ischemic AKI.

Within four hours reperfusion, reactive oxygen species produced during ischemia reperfusion increase endothelial expression of TLR4. HMGB1 released from injured renal tubulesbind the endothelial TLR4, and cause increased adhesion molecule expression. These adhesion molecules facilitate the immigration of leukocytes into the injured outer medulla. HMGB1 binds to TLR4 on these leukocytes, including macrophages, and stimulates the production of maladaptive interleukin 6. In addition, the HMGB1 also stimulates TLR4 on tubules and stimulates the production of maladaptive chemokines and cytokines. See review and Figure 88.2 .

Figure 88.2

The structure of HMGB1. TLR4-HMGB1 in Ischemic AKI. In response to reactive oxygen species (ROS) released during ischemia/ reperfusion, endothelia of the vasa rectae express TLR4 within four hours after reperfusion (a). Renal tubules also express TLR4, but only after 24 hours following reperfusion; renal tubular TLR4 expression is a response to interferon gamma and TNFα (b). Injury also increases renal tubular production of endogenous TLR4 ligands such as HMGB1 (b), and severely injured cells release these ligands into the extracellular space (d). These extracellular TLR4-ligands trigger maladaptive responses. They activate TLR4 on endothelial cells (e) which in turn, express adhesion molecules (f) that facilitate diapedesis of monocytes (macrophages) from blood into the renal interstitial space (g). The endogenous TLR4-ligands (HMGB1) then activate TLR4 on macrophages (h), and tubules (i). The activated macrophages and tubules release maladaptive molecules such as interleukin 6 (j & k) that exacerbate injury. From Lu CY, Winterberg PD, Chen J, Hartono JR. Acute kidney injury: a conspiracy of toll-like receptor 4 on endothelia, leukocytes, and tubules. Pediatr Nephrol 2011. .

The Complex Biology of HMGB1 and TLR4—Promiscous Molecules with Promiscous Partners and Multiple Biologic Effects

Although the HMGB1–TLR4 interaction in ischemic AKI is well documented in the above experiments, much remains to be learned.

The biology of HMGB1 is complex. HMGB1 is expressed by all eukaryotic cells and is highly conserved through evolution. It was originally described as a nuclear protein that enables interactions between DNA and nuclear proteins that regulate transcription. However, in the late 1990’s a search for mediators of shock revealed that HMGB1 elicited lethal inflammation. Antibodies against HMGB1 prevented shock. Subsequent experiments showed that HMGB1 was released by necrotic cells, and actively secreted by leukocytes of the innate immune response. The little inflammation seen after apoptosis, as opposed to necrosis, may result from sequestration of HMGB1 within the nucleus of apoptotic cells. The various protein domains HMGB1 have unique functions as shown in Figure 88.3 . The A and B boxes bind to DNA, and the C box is negatively charged. The proinflammatory effect of HMGB1 may be reproduced by recombinant B box. Recombinant A box peptide is a specific antagonist of the proinflammatory effects. Thus, there is therapeutic potential in using these genetically engineered peptides to either increase or decrease inflammation.

Figure 88.3

Structure function of HMGB1. From article cited in text.

HMGB1 is post-translationally modified both enzymatically and by reactive oxygen species. It also binds endotoxin and nucleic acids. These may change its biological activity.

HMGB1 has seven known receptors in addition to TLR4. In addition to TLR4, only one other receptor, RAGE, has been studied in ischemic AKI. RAGE is thought not to participate in ischemic AKI in mice because its transgenic knockout does not affect disease.

The biology of TLR4 is also complex. In addition to HMGB1 it binds to other DAMPS. These include oxidation products resulting from reactive oxygen species produced during ischemia reperfusion, extracellular matrix components and heat shock proteins as discussed below.

After tissue injury, the extracellular matrix is degraded into low molecular weight fragments. Two of these fragments, heparan sulfate and hyaluronan, activate TLR4, and may participate in ischemic AKI. Low molecular weight heparan sulfates are released when neutrophil elastase degrades heparan sulfate proteoglycans in the extracellular matrix (see review ). Inhibition of neutrophil elastase ameliorated ischemic acute renal failure in rodents, possibily by inhibiting the production of heparan sulfate fragments. Hyaluronan increases in the ischemic kidney. Low molecular weight hyaluronans are released when hyaluronidases from tubules and leukocyes degrade the extracellular matrix. Small hyaluronans stimulate renal tubular cells to produce MCP-1 (a macrophage chemokine), and TNFα (a proinflammatory cytokine) in vitro . Biglycan is another extracellular matrix component that may stimulate TLR4 after tissue injury.

Heat shock proteins (Hsp’s) are major candidates for being the TLR4 ligands during ischemic AKI: different intracellular and extracellular functions during ischemic AKI?

Hsp70. 1 and Hsp70. 3 are two members of the murine heat-shock-70 family. They are over 95% identical to each other. Gp96 is the heat shock protein of the endoplasmic reticulum. The murine and human Hsp’s are highly homologous.

Although these Hsp’s have well known intracellular cytoprotective effects, they also have extracellular functions as cytokines, and particularly as TLR4-ligands. Indeed, Hsp’s have been used as adjuvants in an attempt to immunize experimental subjects against cancer.

Intracellular Heat Shock Proteins are Cytoprotective

Hsp’s70. 1 and 70. 3 expressions in the nucleus and cytoplasm is increased after cell stress. Gp96 expression is increased as well. These proteins have also been implicated in renal ischemic injury. Within one hour of renal ischemia, Hsp’s70. 1 and 70.3 increase by 5x in the S3 segment of the proximal tubule, and gp96 increases in both the S3 segment and the loop of Henle. Therefore, increased intracellular Hsp’s70. 1 & 3 and gp96 may be part of a cytoprotective mechanism during ischemic ARF (for example and see reviews ).

Extracellular heat shock proteins may be endogenous TLR4-ligands that recruit inflammatory responses during ischemic ARF.

There is also mounting evidence that extracellular Hsp’s act as cytokines, and the term “chaperokine” was coined to highlight their dual functions. Most importantly, extracellular Hsp’s activate TLR4 to recruit an inflammatory response. The possibility that extracellular Hsp’s may have a harmful pro-inflammatory role in ARF was proposed in a theoretical paper.

Source of Extracellular Hsp’s

Since Hsp’s are normally intracellular proteins, the question of how Hsp’s are released into the extracellular space during injury needs to be addressed. There are several possibilities.

Firstly, leakage from cells with morphologically evident injury (necrosis). Hsp’s may be released from severely injured and therefore leaky cells. Since Hsp’s are abundant proteins, and their cytokine functions are likely to require very low extracellular concentrations, a small amount of leakage may trigger the self-amplifying inflammatory mechanisms that induce further injury during the “extension” phase of ischemic ARF. Such necrosis would result in the release of intracellular heat shock proteins into the extracellular space where they could activate the endothelium and leukocytes.

Secondly, release from cells without evident morphologic injury. Several such mechanisms have been proposed: One is the secretion of Hsp’s by stressed cells or cells activated by cytokines. A second mechanism is the release of “exosomes.” Exosomes are formed by a process of “reverse” endocytosis. These small particles contain Hsp’s and they activate macrophages and dendritic cells (see review ). A third mechanism is the expression of membrane bound Hsp’s. Although Hsp’s normally reside in the cytoplasm, endoplasmic reticulum, or mitochondria, they may redistribute to the cell surface after stress. Such cell surface Hsp’s activate leukocytes. Altogether there is ample evidence to support the possibility that Hsp’s from injured renal tubular cells could stimulate TLR4 in the absence of morphologic features of cell death that are detectable by light microscopy.

Other endogenous molecules also interact with TLR4, but they are less well studied than HMGB1, Hsp’s and extracellular matrix components discussed above. Fibronectin IIIA is a variant fibronectin that is produced by stressed cells, and is increased during ischemic ARF. β-defensin is found in kidneys stressed by infection, but β-defensin production during ischemic ARF has not previously been examined. Hsp60 is not known to increase after renal ischemia, but might still be released during ischemic ARF and stimulate TLR4. Tamm Horsfall protein may also be a TLR4 ligand. See review. Not only does TLR4 bind to numerous ligands, each ligand may trigger unique biological effects.

Thus, endotoxin and the endogenous TLR4-ligands have different interactions with the TLR4 receptor. Endotoxin interacts with TLR4 in two ways: first, soluble endotoxin may bind the TLR4-MD2 heterodimer. Second, endotoxin may form lipid micelles that intercalate into cell membrane and then bind TLR4. In contrast, all of the endogenous TLR4 ligands identified so far are soluble molecules. Although the hydrophobicity of these ligands may be important, they are unlikely to directly intercalate into the membrane bilayer. Furthermore, some endogenous TLR4 ligands also bind other cell surface receptors in addition to activating TLR4. For example: Hsp’s 70. 1 & 3 and gp96 bind cell surface CD40 and CD91.

Because endotoxin and the endogenous TLR4-ligands have different modes of interaction with the TLR4 receptor, it is not surprising that they elicit different responses in vitro and in a model of autoimmunity in vivo .

Of particular importance for this discussion is the different effect of endotoxin and ischemia on the kidney. Both injure the kidney, but in different ways. When care is taken to prevent hypotension, endotoxin decreases GFR by over 70% in the absence of apoptosis, inflammation, and other morphological changes; this injury is not affected by transgenic knockout of inducible nitric oxide synthase (iNOS). In contrast, murine ischemic ARF, which is accompanied by the release of endogenous TLR4-ligands, is characterized by profound morphologic injury and inflammation (see for example review ). Unlike normotensive endotoxin ARF, ischemic ARF is ameliorated by transgenic knockout of iNOS.

When hypotension is not controlled, endotoxin causes glomerular, in addition to tubular, injury. In contrast, ischemic ARF with release of endogenous ligands, injures tubules, but not glomeruli. Other data shows that systemic endotoxin injures the kidney by increasing the production of extrarenal TNFα.

Note that ARF induced by endotoxin differs from ischemic ARF in another fundamental way: endotoxin is injected systemically and induces massive cytokine production in many organs; on the other hand, during ischemia the postulated TLR4 ligands are released locally in the kidney.

Another example of differences between endotoxin and endogenous TLR4 ligands is a model of autoimmune isletis where endotoxin alone induced diabetes, but Hsp’s 70.1 and 70.3 (both endogenous TLR4 ligands) required additional activating anti-CD40 to induce diabetes. Still another relevant example is the TLR4-dependent abilities of LPS to decrease, but HMGB1, another TLR4 ligand, to increase, the carcinogenicity of croton oil.

In addition to differences between the response of TLR4 to endotoxin versus DAMPS, individual DAMPS may each elicit a unique response through TLR4.

As discussed above, TLR4 recognizes both DAMPs and endotoxin produced by bacteria. Microbial products, such as endotoxin, have hydrophobic domains; these domains are also found on proteins denatured during cellular injury, and on DAMPs such as HMGB1 that are released into the extracellular space. Because DAMP receptors appeared early during evolution, they may have evolved to recognize injury, organize repair, and then later acquired a host-defense role by recognizing microbes. However, the responses to infection and repair have different goals. After recognizing microbes, TLR4 triggers an aggressive inflammatory response where elimination of the pathogen is the overwhelming priority, and collateral damage to self tissue by toxic microbicidal molecules is an acceptable price for survival of the organism; ultimately, repair occurs after cure of the infection. In contrast, sterile injury such as ischemia/ reperfusion, has tissue repair as the priority. The initial maladaptive inflammation may reflect the fact that tissue injury and infection often occur together, especially after trauma and disruption of the skin. A “shoot first, ask questions later” strategy may have evolved because an initial inflammatory response against the possibility of infection best served survival despite some collateral tissue damage. A fundamental question is how, after either infection or sterile injury, the mononuclear phagocytes change from aggressively proinflammatory (maladaptive for ischemic injury) to reparative. This question may be answered, at least in part, by the presence of CD24-Siglec 10 on mammalian but not bacterial cel surfaces. CD24/ Siglec 10 binds DAMPSand turns off the TLR4 response. Bacteria do not express CD24/Siglec 10 and the TLR4 response would therefore not be inhibited. See Figure 88.4 .

Figure 88.4

CD24/ Siglec 10 prevent excessive inflammation after stimulation of TLR4. Pathogen-associated molecular pattern molecules (PAMP), such as endotoxin associated with bacteria, elicits a vigorous response. In contrast, damage-associated molecular pattern molecules (DAMP), such as HMGB1, elicit a response which is inhibited by CD24/ Siglec/10 on the host cell.

(From Liu Y, Chen GY, Zheng P. CD24-Siglec G/10 discriminates danger- from pathogen-associated molecular patterns. Trends Immunol 2009; 30: 557-561. PMCID 2788100.)

Less widely appreciated are recent studies showing that TLR4 participates in repair of non-infectious colitis. Some types of non-infectious pulmonary injury, skin wounding and partial hepatectomy. Whether TLR4 has similar repair functions in the kidney is not known.

Other Multi-Ligand Receptors for other Multi-Receptor DAMPS may Detect Ischemic Injury?

In addition to TLR4, a number of other receptors recognize DAMPS. These recognize injury by a number of pathways including the detection of reactive oxygen species, uric acid, glycolipids, and intracellular stress. These receptors include

CD91 : This is also a receptor for heat shock proteins released by injured cells. It has been targeted as a means of increasing immunity against tumors. In addition to binding heat shock proteins, CD91 also binds α2-macroglobulin, collectin and calreticulin, and is known as LDL receptor related protein. These recognize injury by a number of pathways including the detection of reactive oxygen species, uric acid, glycolipids, and intracellular stress.

TLR2 : TLR2 is related to TLR4 and may also recognize Hsp’s. Mice with non-functional TLR2 are protected from ischemic renal failure. Renal tubules express both TLR2 and TLR4 after severe ischemic injury. TLR2 may also be important in ischemic injury to the liver and heart.

RAGE : Although RAGE is best known as the receptor for advanced glycation endproducts and for its contribution to the secondary complications of diabetes mellitus, including diabetic nephropathy, RAGE also detects molecules released by injured cells, and triggers an inflammatory response.

Uric acid : Weibel Paladi bodies, NALP3, and Pyronecrosis. Uric acid is released from injured cells. During ischemic AKI this may induce endothelia to release proinflammatory Weibel-Palade bodies. Uric acid may also activate Nlrp3, possibly by activating the inflammasome and triggering pyronecrosis.

Complement : Renal IRI does activate complement. Tubular injury decreases expression of basolateral expression of Crry, the murine homolog of human MCP (membrane cofactor protein) and DAF (decay accelerating factor); Crry normally prevents amplification of the alternative complement pathway after “C3 tickover”. In the absence of basolateral Crry during renal IRI, alternative complement activation continues unrestrained and renal tubular injury results.

Why there should be so many ways to detect molecules released by injured cells is not clear. Do all injured cells release the same molecules, are different molecules released after different types of death and injury, do different molecules and receptors elicit different inflammatory responses? In very broad strokes, we will discuss the different modes of programmed cell death and the different inflammation elicited by different types of death later in the chapter. However, a profound understanding of these questions remains to be elucidated by future research.

When Death is no Accident: Necrosis as a Programmed Event

The above section shows that molecules released from necrotic cells elicit an inflammatory response. Necrosis is often considered accidental death. However, a growing body of data indicates that necrosis may also be a programmed event. This suggests that when inflammation is desirable, a cell may be programmed to die a necrotic death, and thus release the pro-inflammatory molecules discussed above.

Poly (ADP-Ribose) Polymerase [PARP] and Programmed Necrosis

The PARP’s are a family of 18 genes. PARP-1 regulates necrosis. That an enzyme regulates necrosis indicates that death is no accident, but is programmed. Pharmacologic inhibition of PARP ameliorates ischemic acute renal injury in rodents. Transgenic knockout of PARP-1 also decreases injury after acute renal ischemia. Inhibition of PARP-1 also ameliorates ischemic injury of the brain and liver.

The best known function of PARP-1 is to repair DNA damage, such as occurs in response to oxidative stress during ischemic acute renal failure. Renal PARP-1 levels increase during ischemic acute renal failure.

It is not intuitively obvious why such a repair enzyme should be required for necrosis. One possibility is that, in the face of massive DNA damage, PARP depletes intracellular NAD + and thus ATP stores. This leads to necrosis, especially in the setting of mitochondrial damage as discussed later in this section. However, necrosis is not necessarily correlated with intracellular energy stores in all model systems. Another possibility is that PARP-1 enhances the activity of NFκB and other pro-inflammatory transcription factors. PARP may also increase mitochondrial release of AIF.

Some suggest that caspases degrade PARP and thus direct cell death down an apoptotic pathway. However, there is decreased ischemic acute renal injury in mice expressing a genetically engineered PRAP-1 that cannot be degraded by caspases.

Cyclophilin D, Mitochondria, and Programmed Necrosis

Another argument that necrosis is regulated comes from studies of mice with transgenic knockout of cyclophilin D. Such mice have decreased necrosis during ischemic acute renal failure. Cerebral ischemia was similarly ameliorated in these knockout animals. These results extend data that cyclosporine, by inhibiting cyclophilin D, ameliorates ischemic injury in some tissues.

Cyclophilin D regulates the mitochondrial permeability transition pore, and the subsequent release of mitochondrial molecules that regulate cell death. The above data suggest an important role for mitochondria in regulating necrosis. Whether opening this pore results in necrosis or apoptosis may depend upon several factors. One is the length of time that the pore is open—transient opening might result in apoptosis; longer opening, necrosis. In addition the availability of ATP may switch the mitochondrial signal from necrosis to apoptosis. This is in line with data showing that lower, more prolonged decreases in ATP are associate with necrosis, while shorter and lesser ATP depletion result in necrosis in renal cells, and that lesser oxidant injury also leads to apoptosis instead of necrosis. Finally, intracellular pH also regulates. The return of the pH from acidic to more alkaline levels with reperfusion makes necrosis more likely.

Additional Examples of Programmed Necrosis in Vivo

We will now review three additional striking examples of the importance of programmed necrosis in vitro .

One example is the host defense against murine vaccinia virus. This virus protects itself by preventing apoptotic programs within infected host cells. In mice with wild type TNFR2, infected cells die by programmed TNFα-mediated necrosis, and elicit a protective inflammatory response. Mice with TNFR2 knockout have a reduced programmed necrosis and thus reduced anti-viral inflammatory response and decreased viral clearance.

The second example is the difference between cerulean pancreatitis in rats versus mice. The worse outcome in the latter is due to greater programmed necrosis. Rats have high apoptosis and low necrosis and thus a better clinical outcome. Mice have low apoptosis and high necrosis and thus a worse outcome with more inflammation. This difference was due to different function of the X-linked inhibitor of caspases (XIAP) in these two species. There was less inhibition of caspases, and thus less inhibition of apoptosis, in the rat by XIAP.

The third example is the exacerbation of shock when apoptosis is inhibited in mice given TNFα. In this case, switching programmed cell death from apoptosis to necrosis had fatal consequences.

After the Suicide, Disposal of the Corpse: Regulation of Inflammation by Macrophages after they Phagocytose Apoptotic Cells

Apoptosis occurs during ischemic acute renal failure. The goal of this discussion is not the regulation of this apoptosis but rather the effect of apoptosis on inflammation. In other words, we discuss phagocytic clearance of the apoptotic cells before their loss of membrane integrity and leakage of the proinflammatory molecules discussed in the previous section. Such clearance is regulated by “eat me,” “don’t eat me,” “come get me” signals.

The surface of the apoptotic cell has “eat me” signals that trigger phagocytosis by macrophages. A major signal is phosphatidylserine that has somehow “flipped” from the intracellular leaflet to the extracellular leaflet of the plasma membrane where it is recognized by macrophage receptors including the phosphatidylserine receptor after bridging by Annexin I. Other less well understood interactions between apoptotic cell and macrophage also contribute to the “eat me” signal. These include sites also capable of binding collectins such as mannose binding protein, C1q, C3b/bi, oxidized LDL, and thrombospondin 1. In addition, the apoptotic cell surface has decreased “don’t eat me” signals such as CD31. Furthermore, phosphatidylcholine on apoptotic cell surfaces is cleaved by phospholipase A2 to form lysophosphatidyl choline which is the best understood chemoattractant “come get me” signal issued by apoptotic cells to macrophages. [See review ].

Under many circumstances, macrophages, which have engulfed apoptotic cells, release anti-inflammatory molecules that prevent further inflammation (for example ). The phosphatidylserine receptor on macrophages may trigger the release of inhibitory cytokines, but this begs the question of why this receptor is not triggered when macrophage phagocytose necrotic debris, including phosphatidylserine on the intracellular side of cell membrane fragments. In the absence of a receptor for phosphatidylserine, macrophages cannot ingest apoptotic cells, and the lungs of such mice fill with cellular debris and inflammation. This may reflect the consequences of overwhelming the phagocytotic system with too many apoptotic corpses as perhaps occurs during ischemic acute renal failure. This situation may reflect “post-apoptotic necrosis” and the release of proinflammatory mediators.

However, there are a number of experimental circumstances where phagocytosis of apoptotic cells results in the release of pro-inflammatory molecules by macrophages, and where ingestion of necrotic debris results in the release of anti-inflammatory molecules. This may reflect the influence of cytokines in the microenvironment, or the redox potential of the microenvironment that can oxidize phospholipids and turn them into macrophage activating signals.

Efferocytosis is the phagocytosis of apoptotic cells and does not cause the release of proinflammatory cytokines. If efferocytosis cannot dispose of all the apoptotic cells, then some will degenerate and release DAMPS. Increasing efferocytos by injections of MFG-E8 (milk fat globule-EGF factor 8/ lactadherin) ameliorates ischemic AKI in rodents; MFG-E8 is a “bridging molecule” that links the apoptotic cells to phagocytes, and thus increases efferocytosis.


The ultimate amount of injury during ischemic AKI is the result, not only of the ischemic insult, but also of the resulting inflammation. In this chapter, we have summarized the current understanding of the major inflammatory processes during ischemic AKI.


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