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driven apoptosis and necrosis during chronic fibrotic lung disease. Keywords: sterile inflammation; epithelium; immune response; bleomycin. Clinical Relevance.
TRANSLATIONAL REVIEW Danger-Associated Molecular Patterns and Danger Signals in Idiopathic Pulmonary Fibrosis Christian D. Ellson1, Rebecca Dunmore1, Cory M. Hogaboam2, Matthew A. Sleeman1, and Lynne A. Murray1 1

MedImmune Ltd, Granta Park, Cambridge, United Kingdom; and 2Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California

Abstract The chronic debilitating lung disease, idiopathic pulmonary fibrosis (IPF), is characterized by a progressive decline in lung function, with a median mortality rate of 2–3 years after diagnosis. IPF is a disease of unknown cause and progression, and multiple pathways have been demonstrated to be activated in the lungs of these patients. A recent genome-wide association study of more than 1,000 patients with IPF identified genes linked to host defense, cell–cell adhesion, and DNA repair being altered due to fibrosis (Fingerlin, et al. Nat Genet 2013;45:613–620). Further emerging data suggest that the respiratory system may not be a truly sterile environment, and it exhibits an altered microbiome during fibrotic disease (Molyneaux and Maher. Eur Respir Rev 2013;22:376–381). These altered host defense mechanisms might explain the increased susceptibility of patients with IPF to microbial- and viral-induced exacerbations. Moreover, chronic epithelial injury and apoptosis are key features in IPF, which might be mediated, in part, by both pathogenassociated (PA) and danger-associated molecular patterns (MPs). Emerging data indicate that both PAMPs and danger-associated MPs contribute to apoptosis, but not necessarily in a manner that

Sterile Inflammation and Danger-Associated Molecular Patterns The loss of cellular membrane integrity observed during necrosis results in uncontrolled release of cellular contents, some components of which can act as danger-associated (DA) molecular patterns (MPs). During normal homeostasis, DAMP-mediated inflammation allows the host to clear the associated cellular debris

allows for the removal of dying cells, without further exacerbating inflammation. In contrast, both types of MPs drive cellular necrosis, leading to an exacerbation of lung injury and/or infection as the debris promotes a proinflammatory response. Thus, this Review focuses on the impact of MPs resulting from infectiondriven apoptosis and necrosis during chronic fibrotic lung disease. Keywords: sterile inflammation; epithelium; immune response;

bleomycin

Clinical Relevance Idiopathic pulmonary fibrosis is a chronic, progressive lung disease that can be worsened with acute exacerbations. It has been hypothesized that chronic injury in the lung contributes to the progressive loss of lung function observed in all patients. However, bacterial or viral infections are rarely detected, even during exacerbation. Therefore, the acute inflammatory response and worsening may be due to microtrauma and endogenous danger signals, and not host defense responses.

and subsequently resolve the inflammation and, where necessary, repair the tissue. However, exaggerated DAMP signaling is the basis of “sterile inflammation,” which is an inflammatory response driven in the absence of an overt infection. Beyond passive release from membrane-compromised necrotic or secondary necrotic cells, some DAMPs can be actively synthesized and released upon sensing of cellular damage or inflammation, and others can be generated by degradation

of signaling-inert molecules into active stimulatory ligands. The receptors for DAMPs are collectively termed “danger receptors,” which often function within pathogen-mediated immunity—for example, the Toll-like receptor (TLR) family. Numerous DAMPs and danger receptors appear to contribute to the pathogenesis of lung fibrosis. Moreover, these pathways are known to contribute to the innate and adaptive immune responses in the lung (Figure 1).

( Received in original form August 19, 2013; accepted in final form April 16, 2014 ) Correspondence and requests for reprints should be addressed to Lynne A. Murray, Ph.D., MedImmune Ltd, Granta Park, Cambridge CB21 6GH, UK. E-mail: [email protected] Am J Respir Cell Mol Biol Vol 51, Iss 2, pp 163–168, Aug 2014 Copyright © 2014 by the American Thoracic Society Originally Published in Press as DOI: 10.1165/rcmb.2013-0366TR on April 21, 2014 Internet address: www.atsjournals.org

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TRANSLATIONAL REVIEW or late) and necrotic (primary or secondary) cells (see Ref. 11). For instance, both apoptotic and necrotic cells stain positive for annexin V, and necrotic cells can also be positive for terminal deoxynucleotidyl transferase dUTP nick end labeling staining (a marker classically used as a marker of apoptosis). Thus, although necrotic cells are rarely reported in the lungs of patients with IPF or in mouse models of IPF, areas of apoptosis likely feature elements of necrosis.

Induction and Inhibition of Apoptosis

Figure 1. Schematic of recognized danger-associated molecular patterns (DAMPs), the receptors to which they bind, and association with the innate and adaptive immune response. DNGR-1, C-type lectin domain family 9 member A; HMGB1, high-mobility group protein B1; NLRP, NACHT, LRR and PYD domains-containing protein; RAGE, receptor for advanced glycation end products; TLR, Toll-like receptor.

Source of DAMPs in Idiopathic Pulmonary Fibrosis: Apoptosis and Necrosis Type II alveolar epithelial (ATII) cell injury is an early feature in the lungs of patients with idiopathic pulmonary fibrosis (IPF), and is thought to be a key driver of the aberrant wound-healing response and pathogenesis of the disease. In patients with IPF, roughly 70–80% of ATII cells stain positive for apoptosis markers, including caspase 3 (1, 2). It is speculated that the combination of genetic, environmental, and age-related factors leaves the epithelium predisposed to injury from factors such as cigarette smoke, environmental exposures, viral and bacterial infection, and microaspiration (i.e., gastroesophageal reflux disease) (3). Moreover, in the IPF lung, endoplasmic reticulum stress and oxidative damage might trigger epithelial cell apoptosis (1). Although the exact cause of epithelial damage may not be readily 164

identified, the loss of these cells contributes to the progression of IPF. The recognition and phagocytosis of apoptotic cells, a process termed “efferocytosis,” occurs in a nonphlogistic or anti-inflammatory manner (4–6). The immunological staining demonstrating an increase in apoptotic markers in the IPF lung may be due to an increase in apoptosis, but also impairment in efferocytosis. The predominant macrophage phenotype in the IPF lung is the M2 macrophage, which generates profibrotic mediators, such as transforming growth factor (TGF) b, and is also not very effective at degrading cellular debris intracellularly (7–9). Consistent with this, delivery of apoptotic cells into the lungs of naive mice promotes TGF-b production and resolution, whereas necrotic cells introduced in the same manner drive an inflammatory response and abnormal remodeling (10). It is relevant to note overlap in the observable “phenotypes” of apoptotic (early

Animal models have indicated that both apoptosis and necrosis drive a positivefeedback loop that exacerbates the underlying fibrotic remodeling and fibrotic milieu during renal and cardiac fibrosis (12, 13). In the lung, inhibiting apoptosis with a broad-spectrum caspase inhibitor attenuated downstream TGF-b–induced lung fibrosis (14). Moreover, models that damage or denude the epithelium (such as intratracheal bleomycin), or genetic depletion of ATII cells (using toxinbased approaches), results in collagen accumulation and a fibrotic response in the lung (15). Innate immune signaling in the context of the bleomycin model appears to have a direct role in the severity of the fibrotic response. Bleomycin is a glycopeptide-polyketide antibiotic that inflicts cellular injury, such as reactive oxygen species–dependent and –independent DNA damage. How well this acute injury model reflects chronic human IPF is widely debated. However, specific cellular alterations in the bleomycin model have been shown to mimic changes observed in IPF, such as bleomycin model–derived fibroblasts and IPF fibroblasts, both diverting apoptosis signaling via the TNF receptor–associated factor and NF-kB (16). The immediate response to bleomycin is an acute inflammatory response, which gives way to a profibrotic phase, ultimately followed by resolution (17). Often, blockade of a danger signaling axis in the initial proinflammatory phase ameliorates the fibrosis. As anti-inflammatory drugs are broadly ineffective in treatment of human IPF, it can be argued that these models will not illuminate therapeutic avenues, but do underscore that early sterile inflammation

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TRANSLATIONAL REVIEW may be an initiating driver of the pathology. However, there is much to be learned regarding the role of MPs in fibrosis, as the deletion of a number of DAMP signaling axes results in a worsening of the fibrotic response, suggesting a positive role for these pathways in the resolution phase. These studies are further discussed subsequently here.

DAMP Signaling in Lung Fibrosis Deleterious Proinflammatory Pathways

A number of danger signaling axes have been shown to be deleterious in lung fibrosis, including TLR2, uric acid, ATP, and IL-33/ST2. During infection, TLR2 recognizes a range of PAMPs most commonly associated with gram-positive bacteria. After bleomycin, TLR2-deficient mice are resistant, with reduced inflammation and fibrosis (18, 19). Bone marrow chimera experiments demonstrate that disease-relevant TLR2 is resident on lung epithelial cells rather than immune cells (18). The endogenous DAMP responsible for TLR2 activation in this model is unknown, although levels of highmobility group protein B1 (HMGB1) and hyaluronan fragments (both proposed TLR2 ligands) are elevated in bleomycintreated lungs (19, 20). It has also been suggested that bleomycin is a direct agonist of TLR2 (21), although these experiments did not exclude an indirect TLR2 stimulation through bleomycin-induced release of danger signal(s). Dead and dying cells also produce large amounts of the purine catabolite uric acid. This uric acid can locally crystallize and act as a danger signal to activate the NACHT, LRR and PYD domainscontaining protein 3 (NALP3) inflammasome, leading to IL-1b production, inflammation, and fibrosis (22). Administration of exogenous uric acid crystals induces pulmonary inflammation, whereas blocking uric acid accumulation reduces inflammation. The inflammation resulting from administration of uric acid crystals appears to be redundantly dependent on TLR2 and TLR4, and on myeloid differentiation primary response 88 and IL-1R (22). Similar to uric acid, intracellular ATP is also released upon cellular injury; bronchoalveolar lavage (BAL) from patients with IPF and bleomycin-treated mice contains Translational Review

increased levels of ATP in comparison to control samples (23). Moreover, blocking P2X7 reduces the inflammatory and fibrotic markers, whereas administration of stable ATPgS exacerbates the pathology (23). Another recent observation is the potential profibrotic role of IL-33. This cytokine is released upon cell death, and is thus referred to as an “alarmin” or danger signal (24). IL-33 levels have been shown to correlate with a number of fibrotic pathologies, including human and mouse liver fibrosis (25), as well as elevated levels directly correlating with an impairment in lung function in systemic sclerosis (26). IL-33 induces T helper type 2 cytokines in vivo and in vitro, and in vivo the IL-33 receptor, ST2, is up-regulated in bleomycin models (27, 28). Protective Danger Signaling Axes

Other DAMP pathways have been shown to be protective, whereby defective danger signaling can result in a worse IPF prognosis. TLR4/TLR2–deficient mice have decreased cytokine production and immune cell infiltration, but increased tissue damage and mortality in response to bleomycin (20). Similarly, mice deficient in both TLR2 and TLR4 are also more sensitive to radiation-induced pulmonary fibrosis (29). Deletion or blockade of TLR4 results in an ultimate failure to appropriately resolve bleomycin injury, and increases mortality (30). In response to bleomycin, TLR4-deficient mice have a lung environment that is skewed toward immunosuppression, and inhibits autophagy-dependent clearance of collagen. Conversely, administration of TLR4 agonists rescues wild-type (WT) mice from the effects of bleomycin-induced lung injury and fibrosis. Numerous endogenous molecules have been reported to be TLR4 agonists, including HMGB1 (31), S100 proteins (32), and heat shock protein 60 (33), as well as various matrix components, including tenascin c (34, 35), hyaluronan fragments (20), fibronectin (36), and fibrinogen (37). However, not all of these molecules have been implicated in IPF, and care must be taken when interpreting studies where contaminating LPS (endotoxin) may lead to experimental artifacts. HMGB1 is the moststudied TLR4 DAMP, and is elevated in BAL from patients with IPF and in the bleomycin model. Blockade with an anti-HMGB1 antibody after bleomycin administration resulted in less severe fibrosis (38), although this effect is not

necessarily attributable to TLR4, as HMGB1 also signals through TLR2 and receptor for advanced glycation end products (RAGE; see subsequent text). It has been shown recently that thrombinmediated digestion of fibrinogen yields proteolytic fragments that can stimulate TLR4 activity (39). As thrombin activity has been shown to be elevated in the BAL of patients with IPF (40), this may represent a form of danger signaling. TLR3 is a cognate receptor for PAMPs, including viral double stranded RNA (dsRNA), but also acts as a danger receptor for endogenous RNA released from dying cells (41). In IPF, TLR3 may be acting as a PAMP receptor, as dsRNA is commonly found in IPF BAL (42). A TLR3 polymorphism, Leu412Phe, which is defective in ligand-stimulated cytokine production and inhibition of fibroblast proliferation, has been shown recently to associate with rapidly progressing IPF (43). Increased susceptibility of TLR3-deficient mice in the bleomycin model supports a protective role for TLR3 function, due in part to its role in the generation of IFN-b, which has potent antifibrotic properties (43). During bleomycin, constitutive TLR9 expression in immune cells protects from fibrotic injury; TLR9 agonism is protective, whereas TLR9-deficient animals have enhanced fibrosis compared with WT mice (44). In contrast to these mouse studies, elevated TLR9 in IPF lung tissue is largely localized to stromal and not immune cells (45, 46). Furthermore, fibroblasts isolated from patients with IPF show elevated expression of TLR9, and TLR9 levels distinguish between rapid and slow progression of disease. TLR9 activation in IPF fibroblasts promotes de novo a-smooth muscle actin expression, suggesting TLR9 as a driver of myofibroblast differentiation. Although the role of TLR9 in human IPF progression has focused on microbial dsDNA during exacerbation, mitochondrial DNA from compromised cells might also activate TLR9, as is the case in severe tissue trauma (47) and cardiac failure (48). More studies are required to dissect the role of TLR9 in fibrotic progression and between the experimental (in which TLR9 is largely restricted to immune cells) and human (in which TLR9 is mostly expressed by nonimmune cells) settings. RAGE is a danger receptor that is expressed at high basal levels in the lung. Patients with IPF have decreased levels of 165

TRANSLATIONAL REVIEW RAGE expression in the lung, as do the lungs of mice treated with bleomycin and other fibrotic agents (49). However, RAGEdeficient mice develop age-dependent fibrotic lung disease and enhanced fibrosis in response to asbestos challenge (50). In contrast, RAGE-deficient mice are protected from bleomycin, although treatment of WT animals with soluble RAGE to block signaling does not alleviate fibrosis. These apparently paradoxical results indicate differential roles for RAGE, and further work is needed to determine the role RAGE in IPF. Adaptive Immune Responses to DAMPs

In IPF, the role of DAMPs has largely concentrated on the innate responses that occur immediately after receptor activation, focusing on NF-kB signaling and the role of HMGB1, IL-1, and IL-33 in promoting inflammation and fibrosis (51). However, given that IPF is thought to exist subclinically for a number of years, there might be a role for an autoimmune response to neoantigens after epithelial injury or necrosis. Autoimmune diseases such as rheumatoid arthritis are characterized by autoantigens to either intracellular proteins or extracellular matrices, and the presence of autoantibodies directly correlates with progression of joint destruction (52, 53). Although IPF is not a bona fide autoimmune disease per se, autoantibodies to a number of epithelial-derived antigens have been described in IPF, and, in some

cases, correlated with disease severity (54–59). The manner in which autoantibodies contribute to lung damage is not clear, although complement deposition is likely to play a role (55, 60). In addition, there is also evidence in IPF that there is an overrepresentation of the major histocompatibility complex genes (61). Although the immune response in IPF has been considered of lower relevance, due to the lack of clinical response observed with standard immunosuppressive agents, there is new evidence that the immune response has a role in IPF. Tissue explants and surgical lung biopsies have aggregates of B and T cells (60, 62), activated T lymphocytes (63), and mature dendritic cells (64, 65). In addition, T cells isolated from subjects with IPF proliferate in response to autologous tissue aggregates and release profibrotic mediators, such as IL-10, TGF-b, and TNF-a (66). The proportion of plasma B cells is also increased in IPF, and correlates with pulmonary arterial pressure. In addition, the plasma concentration of B cell survival factor, B lymphocyte stimulator, is also elevated, and correlates with poor outcome (60). A direct role for B cells in fibrosis remains controversial (67); however, CD19deficient mice are protected from systemic bleomycin challenge (68, 69), suggesting that B cell signaling may also contribute directly to the fibrosis. In addition to CD4 T cells, a population of CD8 T cells has been reported in the IPF lung (70–72), and their numbers correlate with pulmonary arterial pressure and dyspnea scores.

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Finally, it has recently been shown that dendritic cells can phagocytose necrotic cells and cross prime CD8 T cells (73) via cell-associated antigens (74), using the Ctype lectin 9A (or DNGR1). Thus, after epithelial death and necrosis in the fibrotic lungs, cellular DAMPs might be crosspresented, leading to CD8 activity and lung damage. Although many of these associations do not directly point to autoimmunity, they do suggest that an active adaptive immune response driven by DAMPs is integral to IPF progression.

Conclusions There is strong evidence for the presence of MPs and danger signaling during pulmonary fibrosis. In IPF, the unrelenting tissue remodeling response, coupled with unknown triggers of exacerbation, suggest a form of sterile inflammation that is impervious to currently available antiinflammatory and immunomodulatory therapies. Given that pathways evoked by this system can be protective or deleterious in mouse models, therapeutic targeting of these axes in human disease should be viewed with caution. However, there is much to be learned regarding the nature of the MPs that are present locally and systemically in IPF, and the manner in which these factors alter the activation of lung immune and resident cell populations. n Author disclosures are available with the text of this article at www.atsjournals.org.

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American Journal of Respiratory Cell and Molecular Biology Volume 51 Number 2 | August 2014