American Journal of Respiratory Cell and Molecular Biology

Elafin and secretory leukocyte protease inhibitor (SLPI) are pleiotropic molecules chiefly synthesized at the mucosal surface that have a fundamental role in the surveillance against microbial infections. Their initial discovery as anti-proteases present in the inflammatory milieu in chronic pathologies such as those of the lung suggested that they may play a role in keeping in check extracellular proteases released during the excessive activation of innate immune cells such as neutrophils. This soon proved to be a simplistic explanation, as other functions were also soon ascribed to these molecules (antimicrobial, modulation of innate and adaptive immunity, regulation of tissue repair). Data emanating from patients with chronic pathologies (in the lung and elsewhere) have shown that SLPI and elafin are often inactivated in inflammatory secretions, either through the action of host or microbial products, justifying attempts at antiprotease supplementation in clinical protocols. Although these have been sparse, proof of principle has been demonstrated, and future challenges will undoubtedly rest with improvements in methods of delivery in the context of tissue inflammation and in careful selection of patients more likely to benefit from SLPI/elafin augmentation.

Despite the inherent difficulties of targetting drugs to the inflammed lungs, the very pleiotropic activity of secretory leukocyte protease inhibitor and elafin (antibacterial, adjuvanticity at mucosal defences, anti-protease) suggest that these molecules should be of interest to pharmaceutical companies and pulmonologists seeking solutions to treat infective exacerbations of inflammatory lung diseases.

The mucosal surfaces are the first barriers against infections and have an essential role in the prevention of systemic dissemination of pathogens. To achieve this role in a naive host, lung epithelial cells and alveolar macrophages sense pathogens through an array of pathogen recognition receptors such as Toll-like receptors (TLRs) and non-TLR receptors such as lectin/collectin molecules and scavenger receptors. This interaction leads to the synthesis of antimicrobial molecules with direct cytotoxic activity against pathogens as well as that of cytokines/chemokines, the role of which is to mobilize other phagocytes such as neutrophils, as well as inducing protective immune responses. Neutrophils, however, have, upon activation, considerable potential to cause collateral damage and harm host tissues, in particular through the release of numerous proteases such as neutrophil elastase (NE), cathepsin G, proteinase-3, metalloproteases, and cysteine proteases (16). It seems therefore important for the host to protect itself by producing antiproteases. The latter have been classified as “systemic” or “alarm” depending on their site of production (7).

Liver-derived antiproteases such as α1-proteinase inhibitor (A1-Pi) and α1-antichymotrypsin are also important inhibitors of neutrophil enzymes NE and cathepsin-G. The present review will deal chiefly with the alarm serine-protease inhibitors secretory leukocyte protease inhibitor (SLPI) and elafin, which can be considered mostly as mucosal and locally produced defense molecules (8). Throughout this review, we will only use the term “SLPI” to describe the former, but will indistinctively, unless specified, use the terms “elafin” or “trappin-2” to describe the latter.

SLPI and elafin have been purified and characterized in a period of time spanning the late '70s to the early '90s under a variety of names (to name a few: bronchial inhibitor [BrI], mucosal proteinase inhibitor [MPI], antileukoprotease [ALP], human seminal plasma inhibitor [HUSI-I] for SLPI [913]; or BSI-E, elastase-specific inhibitor [ESI], precursor of elafin-ESI [PELESI], skin-derived antileukoprotease [SKALP], trappin-2, for elafin [1421]). They (or their orthologs) are found in invertebrates (22) and verterbrate lineages, even though most the studies have concerned mammalian species (23, 24). They have been described in fetal (25, 26) as well as in adult tissues.

They are members of the WAP (whey-acidic protein) family of molecules, the latter being a major component of the whey fraction of milk. WAP proteins share limited sequence identity, except for their conserved cysteine-rich regions, known as 4-disulphide core (4-DSC) domains, and the positional conservation of specific residues (2729). SLPI and trappin-2 are two low-molecular-weight secreted proteins (Mr 11.7 and 9.9, respectively), and they are heavily disulfide-bonded (8 and 4 C-C, respectively), with a high net positive charge (+11 and +7, respectively). SLPI contains two WAP domains, with its antiprotease activity residing in its second C-terminus WAP/4-DSC domain, while elafin is composed of two regions: a globular C-terminus WAP/4-DSC domain structurally similar to that of SLPI and also endowed with the antiprotease activity, and a flexible NH2 domain referred to as “cementoin,” or “trappin” domain (hence one of the acronyms), which provides a substrate for the enzyme transglutaminase (30, 31). This enzyme allows elafin to be cross-linked into polymers or with extracellular matrix components (32, 33).

Their spectrum of protease inhibition is slightly different: indeed, SLPI has been shown to inhibit NE, cathepsin G, trypsin, chymotrypsin, tryptase, and chymase, whereas trappin-2 possesses a narrower spectrum of inhibition, only inhibiting NE and proteinase 3, which justified the use of one of its earliest acronyms as “elastase-specific” inhibitor (ESI) (34).

As some of their acronyms suggest, the source of SLPI and elafin are mainly the body mucosae and the skin, although they have also been isolated from the joint (3437). Logically, they were therefore purified mostly from highly inflammed mucosal secretions, where neutrophilic inflammation is prominent (e.g., the respiratory tract of patients suffering from chronic obstructive pulmonary diseases [COPD], cystic fibrosis, and psoriatic skin).

All the above seemed to make perfect sense at the time of their discovery and left us until the early nineties with the self-righteous feeling that all was done and dusted. SLPI and elafin are, after all, protease inhibitors and their only role in life, surely, is to provide a coverage against extracellular proteases spilling out from maladaptive excessive activation of neutrophils?

However, data soon accumulated showing that it was not that simple and that SLPI and elafin exerted their activities potentially through a variety of mechanisms (see below).

Among the panel of cytokines/mediators tested to study the regulation of SLPI in lung cells, “alarm” signals such as bacterial LPS, IL-1β, TNF-α, neutrophil elastase (8, 3840), and corticosteroids (41) were shown to switch on the production of these inhibitors in epithelial cells. IL-1 and TNF were shown to produce similar increases of elafin in lung cells and keratinocytes in vitro and the downstream signaling pathways were dissected as being c-jun, p38 mitogen-activated protein kinase, and NF-κB (4244). In the skin, SLPI expression has also been shown to be under the dependence of the EGF-R pathway (45, 46).

Hormones were also shown to influence SLPI production in a breast epithelial cell line (4749), in keeping with the observed variations of SLPI and elafin levels throughout the menstrual cycle.

In addition, and in relation to their additional role as antimicrobial molecules (see below), defensins, another class of innate defense molecules with antimicrobial activity, were also shown to up-regulate SLPI and elafin and share the same signaling pathways (50).

Myeloid cells follow a different path: although LPS can induce SLPI expression in macrophages, anti-inflammatory cytokines such as IL-6 and IL-10 induce the inhibitor in macrophages with delayed kinetics (51) and notably, in return, SLPI can up-regulate macrophage production of the anti-inflammatory cytokines TGF-β and IL-10 (52).

Comparatively much less is known about the mediators able to down-regulate SLPI expression in epithelial cells, although TGF-β was shown to be effective in vitro (53).

Although their inherently “solid” molecular structure (heavily disulfide-bonded) makes these inhibitors quite resistant to proteolysis, some studies show that both host and microbial (see below) proteases can partially degrade them. Notably, proteinase-3 and cysteine proteases such as cathepsin B, L, and S were shown to be active against SLPI (54, 55) and more recently elafin was also shown to be cleaved in presence of excess NE (56).

Whether these cleavages confer additional properties to the molecule is still unknown and may be an interesting issue to consider (see discussion below).

As mentioned above, these molecules are mainly derived from the mucosae and in particular from epithelial cells and cells lining body cavities, as well as inflammatory cells (see Ref. 34 for a review).

Because they are extracellular antiproteases, their most obvious mode of action, and the first described, was thought, as indicated above, to be through the inhibition of their target enzymes (e.g., NE and trypsin) acting extracellularly on matrix molecules or at cellular surfaces through receptors such as TLR-4 and PAR (protease-activated) receptors. However, whether the action of proteases on these receptors activates or deactivates cells is still a matter of controversy (5760).

However, equally compelling data started accumulating showing that SLPI and elafin had anti-inflammatory activities not necessary linked to their ability to inhibit extracellular proteases. Indeed, we and others showed that overexpression of either SLPI or elafin inhibits the activity of the transcription factors NF-κB or AP-1, through as-yet-undefined mechanisms (61, 62). Because these results were obtained in transfection (transient or stable) experiments, one wonders: how “in real life” could SLPI and elafin, essentially extracellularly secreted molecules (as mentioned above), gain access to intracellular compartments to alter transcriptional events? Although it has not been tested, to our knowledge, for elafin, it has been shown that extracellularly added labeled SLPI was retrieved from primary monocytes and U937 cell DNA and was able to inhibit NF-κB activity by binding to DNA NF-κB sites (63), echoing early data showing that SLPI can bind to DNA (64, 65) and suggesting that trafficking of SLPI to the nucleus from the extracellular compartment was possible. How can such a transfer occur? A bona fide cellular receptor for SLPI or elafin is yet to be described, suggesting that SLPI (and elafin if such a similar effect was to be described) may be able to cross membranes. This is of course not without precedent (6668) and may indeed be a feature of the molecule cationic nature and its high lysine and arginine content, which would allow it to interact with negatively charged membranes. In line with this, SLPI has been shown to bind to annexin II and scramblase (69, 70).

Whatever their mode of action, either by inhibiting extracellular proteases, or by inhibiting intracellular transcription factors activation, or a combination of both, in vivo experimental proof of their anti-inflammatory/pro-apoptotic activities abound in the lung, and also in a variety of organs (for a review see Refs. 34 and 71). In addition, data also exist showing that SLPI can promote repair of injured tissues, potentially implicating NE as a fibrotic agent (72), suggesting a continuum of activities from the regulation of excessive tissue injury to the re-establishment of homeostasis (34; Figure 1).

As mentioned above, these anti-inflammatory activities are not the only features of SLPI and elafin. Importantly, their status as important defense molecules was further confirmed by the demonstration, in addition to the activities described above, of their in vitro antimicrobial activity against a variety of micro-organisms such as Staphylococcus aureus, Pseudomonas aeruginosa, Eschercichia coli, Klebsiella pneumoniae, Haemophilus influenzae, Streptococcus pneumoniae, Branhamella catarrhalis, Aspergillus fumigatus, Candida albicans, Mycobacterium tuberculosis (7377), HIV (7881), and the demonstration that defensins could increase SLPI and elafin production (50), suggesting synergy between these two important families of molecules.

Experimentally, we confirmed the direct in vitro (7476) antibacterial activity of elafin in vivo by showing that overexpression of adenovirus-mediated elafin in mice lungs (a natural KO for this molecule) provided protection in P. aeruginosa and S. aureus models of lung infection by down-regulating both bacterial load and excessive neutrophilic inflammation (82, 83).

The in vitro antibacterial activity of SLPI and elafin may be due to their cationic charge as for defensins (73, 74, 76), but recent data suggest that in vivo, bacterial virulence may be dependent on protease activity, which could be (although not demonstrated formally) a target of SLPI and elafin (8486).

Significantly, and showing the importance of the interface SLPI/elafin-microbes, several reports demonstrate in particular that bacteria (8789), parasites (90), viruses (91), and even house dust mites (92) have evolved strategies to down-regulate/suppress the expression of these molecules.

The findings described above are in accordance with a role of these molecules in the maintenance of a relative tolerogenic phenotype at mucosal surfaces such as those of the lung both at the steady state and in inflammatory situations as well as a role in the restoration of homeostasis. In addition to the direct down-regulating effects on innate immune cells discussed above, SLPI may play a role in adaptive immunity through maintenance of mucosal tolerance threshold, since it has been described in the murine cervical lymph nodes (which drain the nasal mucosa) but not in peripheral lymph nodes (93). In addition, it has been suggested that SLPI may be involved in the mucosal epithelial regulation of IgG and IgA class switching (94). Although its function in lymph node cell types has not been studied in detail, to our knowledge, the dendritic cell could be one of its targets as we and others have shown that purified neutrophil elastase (one of SLPI's targets) can “de-activate” and/or “bias” ex-vivo DC toward a regulatory phenotype (95, 96). Furthermore, intriguingly, γδ T cell clones have been shown to produce elafin, and not other antimicrobial molecules (97).

It will not have escaped the reader's attention that so far throughout this review, SLPI and elafin have hardly been mentioned in isolation but rather as a unit able to perform, indistinctively and almost indiscriminately, the functions discussed, be it anti-inflammatory, antimicrobial, or immune-regulatory. Are SLPI and elafin merely redundant molecules? It may be so, but at least not in mice, since the latter have a SLPI equivalent but do not have the gene for elafin (34). Indeed, there may be some important differences between these two molecules, aside from their differential structure and spectrum of enzymatic inhibition already discussed. Generally speaking, the levels of SLPI recovered from inflammatory secretions are clearly higher than those of elafin. This, and the fact that SLPI seems less responsive to inflammatory cytokines when compared with elafin (8), suggests that SLPI may provide a constitutive anti-inflammatory/tolerogenic shield to the lung, while proinflammatory cytokinic stimulation may induce the appearance of elafin to consolidate effects or, in a stimulus-dependent fashion, endow new functions to the lung mucosa.

Indeed, we have only discussed so far the potential for these molecules to “cool down” inflammatory and immune processes. Interestingly, we have also shown more recently that with certain agonists such as LPS or viruses, elafin can have a proinflammatory “adjuvant” activity that promotes the engagement of the innate (98100) and even adaptive immune system (101). More recently, using WT and CD14 KO mice, Wilkinson and coworkers have further demonstrated the opsonic activity for trappin-2 against P. aeruginosa, both in vitro and in vivo (102). This “pro-adjuvant” activity is specific to elafin and has not been described, to our knowledge, for SLPI. These apparently conflicting activities (anti-inflammatory in certain conditions, proinflammatory in others) may suggest that elafin could increase clearance of bacteria at early stages of infection by promoting opsonisation/phagocytosis/direct killing of bacteria and neutrophil or dendritic cell early chemotaxis (98102), through mechanisms not fully deciphered, while down-regulating neutrophil and macrophage responses later on during the infection to keep inflammation in check (Figure 1). This dual activity is also found with defensins and cathelicidin (34), and suggests that this class of molecules is also ideally placed, at the microbe–epithelial cell interface, to perform these ying-yang activities. Are these functional differential activities potentially explained by the environment, (i.e., differential cellular targets, intercellular milieu) or by alterations in the molecular structure of these molecules?

Indeed, as mentioned above, SLPI and elafin are grossly organized into two domains, two WAP N- and C-terminal domains for the former, and an N-terminal cementoin domain and C-terminal WAP region for the latter. As stated before, while the antiprotease activity lies in the C-terminal WAP domain in both molecules, their respective N-termini have additional functions, potentially linked to their cationic nature. Hiemstra and colleagues formally demonstrated that the antimicrobial activity of SLPI lies in the N-terminus of the molecule (73), while it was shown that, similarly, the trappin-2 N-terminus domain seems to have most (but not all) the antibacterial and bacterial LPS-binding activities (74, 100) and that this antibacterial activity was independent of antiprotease function (76). Interestingly, Guyot and coworkers have demonstrated in vitro that the enzyme tryptase (103) is able to convert the 9.9-kD trappin-2 molcule into the 6.0-kD WAP domain molecule, possibly explaining the occurrence of variable fragments of trappin-2/elafin when the molecule was first isolated in vivo from the skin and a variety of mucosal secretions. Whether this tryptase-driven conversion is pathophysiologically relevant is still currently unknown, but this cleavage could potentially uncouple, for example, direct antimicrobial activity and effects on host cells, as it is the case for the bactericidal/permeability-increasing protein (BPI) and lung collectins (104, 105).

Equally important factors to consider in interpreting data are the concentrations of SLPI and elafin and the biological milieu bathing these molecules. Indeed, the in vitro and in vivo proinflammatory opsonic and immunomodulatory effects are generally observed with cytokine-like nanomolar range concentrations, which are not directly antimicrobial (7476). In addition, when experiments were performed in vitro, the latter results were obtained only in serum-free conditions, but they may nevertheless have important physiological bearing, as our in vivo results demonstrate, since mucosae such as those of the lung have, at the steady state, low concentrations of serum-derived opsonins.

The array of functions ascribed to these molecules so far clearly demonstrate that SLPI and elafin could lobby with no questions asked, for at least partial membership in the emerging club of “alarmins” (106)! However, their primary structure has no homology with the chief alarmins, the defensins, which are also mainly epithelial cell–derived, compact disulfide-bonded molecules with similar functions, with SLPI and elafin having an extra edge with their additional antiprotease functions (Figure 1).

The array of activities described so far logically prompted investigators from the late '80s to the present to address the therapeutic potential of SLPI and elafin in patients. Indeed, the idea of antiprotease supplementation goes back to the mid-1960s with the seminal discoveries (107) that a subset of patients with emphysema were genetically deficient in α1-antitrypsin (renamed since then α1-proteinase inhibitor, in view of its large spectrum of inhibition). Although it is not the scope of this article to review numerous supplementation studies done with A1-Pi, we refer the reader to recent reviews on the subject (108, 109). Soon after, conditions other than COPD and emphysema, such as cystic fibrosis, were included in that paradigm (110, 111), spurring the birth of the proteinase–antiproteinase imbalance theory, which to this day still offers a theoretical framework for understanding the pathophysiology of many inflammatory conditions.

When comparing the therapeutic potential of SLPI and/or elafin versus A1-Pi, at least three questions remained to be answered. (1) Why would SLPI and elafin a priori be as good/better candidates than A1-Pi in pulmonary chronic inflammatory conditions? (2) Are SLPI and elafin levels modulated in these conditions? (3) Does the inflammatory milieu in pulmonary conditions allow for antiprotease supplementation?

Several arguments allowed investigators to postulate that indeed, SLPI and elafin may be better candidates. Size may matter, as they are smaller molecules and this may confer on them better diffusibility and kinetic properties in vivo (34, 112115). Also, SLPI and elafin (especially the latter) have a much narrower spectrum of inhibition, as indicated above, theoretically allowing for a more focused and safer action.

The second question has been more difficult to address, but several studies have shown that the levels of SLPI are decreased/modulated in COPD, emphysema, and cystic fibrosis (56, 116122) as well as decreased in exacerbations in patients with COPD (123), suggesting that supplementation may be beneficial in that setting.

Also, in two completely different pathologies, ARDS and in farmer's lung disease, even though antigenic SLPI and elafin levels were found to be greatly increased in bronchoalveolar lavage compared with that of control subjects, the ratio of total inhibitory activity versus total antigenic levels of inhibitors was shown to be always very low, suggesting (despite increased levels) that functional inactivation in vivo was occurring (32, 124). The answer to the third question is therefore still crucial as other in vitro data discussed above showed that the inflammatory milieu (oxidants and proteases) can indeed inactivate protease inhibitors activity (125).

Notably, the lung does not stand alone as a potential therapeutic target for SLPI and elafin, as patients with digestive tract disorders have been described with reduced levels of these inhibitors: subjects with active Helicobacter pylori–induced gastritis showed reduced SLPI secretion in stomach (89) and patients with intestinal bowel diseases may have a similar deficit in both SLPI and elafin (126).

Altogether, therefore, enough data showing SLPI and elafin in vivo inactivation are available to justify attempting SLPI supplementation therapy. Although studies showed proof of principle in vivo, in rodents as well as in sheep (127131), few studies, to our knowledge, have been attempted in humans. However, its feasibility has clearly been established and active levels of SLPI in ELF of patients (COPD and CF) have been recovered after aerosolisation, both in central and peripheral airways (132134). In one of these studies, molecular and cellular inflammation was assessed, and SLPI aerosolization was shown to be beneficial (133).

Irrespective of these earlier studies, in addition, the search for mutations or polymorphisms will give the investigators an extra edge and more tools to determine which group of patients may benefit most from SLPI and/or elafin supplementation. To our knowledge, the description of SLPI SNPs is still sparse; however, one study screening 228 alleles in 114 individuals showed the absence of polymorphisms in the coding region (135).

As far as elafin is concerned, a recent study has shown lower levels of elafin in the serum of patients at risk of developing ARDS (136), prompting the same team to study genetic polymorphisms in a cohort of 449 patients with ARDS and 1,031 critically at risk ill patients. They demonstrated a significant association between certain elafin polymorphisms and risk for ARDS, but did not demonstrate a correlation with mortality (137).

In different settings, a study also identified genetic variants in the elafin gene, hypothesizing a potential link with preterm premature rupture of membranes of the amniotic sac in African-American individuals (138), while another study performed in the skin showed that elafin gene polymorphisms were not associated with pustular forms of psoriasis (139).

Since the early '90s, numerous gene therapy protocols have been applied to many organs in an attempt to circumvent the problems linked to repetitive protein administration (cost, reduced half-life, etc.), which are obviously worrisome for chronic diseases. The lung is no exception (140146), and results have been mixed, due to mucus barriers, the relative inefficiency of delivery (in the case of liposomes), or toxicity and induction of immune responses, in the case of virus vectors such as adenoviruses (147). Although results are overall disappointing, vectorology is a never-ending process and improvements in vectors and novel ways of delivery are in the pipeline (148).

A new kid on the block in terms of gene delivery may be the use of genetically engineered probiotics and commensals, which are likely to be less immunogenic. They have been shown already to be safe and efficient as delivery vectors of anti-inflammatory cytokines at mucosal surfaces (149) including those of the lung (150152), and we are currently pursuing the latter line of investigation with the generation of recombinant L. lactis expressing SLPI and elafin and are currently performing experiments to validate their activity in vitro and in vivo (153).

Many mechanistic studies at the molecular level have shown that SLPI and elafin, once thought as monodimensional antiprotease/anti-inflammatory compounds, have in fact multiple functions as guardians of mucosal surfaces, including that of the lung. Their late discovery in the '80s to '90s has no doubt contributed to the relative paucity of studies, and has so far twarthed their integration in the therapeutic arsenal of the pneumologist.

Their very pleiotropic activity (antibacterial, adjuvanticity at mucosal defenses, antiprotease) may have somehow slightly clouded the picture. However, one hopes that despite the inherent difficulties of targetting drugs to the inflammed lungs, as reviewed above, new advances in vectorology and the inherent characteristics of SLPI and elafin should be of interest to pharmaceutical companies and pulmonologists seeking solutions to treat infective exacerbations of inflammatory lung diseases.

The author thanks the Salvesen Emphysema Research Fund, the British Lung Foundation, the Wellcome Trust, and the Medical Research Council (MRC) for funding the work from his laboratory mentioned here. In addition, the author thanks the many colleagues from the MRC Centre for Inflammation Research (Edinburgh, UK) and the Department of Pathology (McMaster University, Hamilton, ON, Canada) who contributed to some of the work described in this review (e.g., A. J. Simpson, J. W. McMichael, K. Hayashi, G. MacLachlan, P. A. Henriksen, T. I. Brown, G. A. Cunningham, A. Silva, M. E. Marsden, T. A. Sheldrake, A. Harris, L. A. Farrell, S. E. Williams, A. Roghanian, A. P. Ryle, J. Gauldie, and C. Haslett). Extended thanks also go to the author's main collaborators thoughout the years (J. R. Govan, Y. V. Kotelevtsev, D. D. Collie, J. R. Dorin, Z. Xing, J. Gauldie, M. Chignard).

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Correspondence and requests for reprints should be addressed to Jean-Michel Sallenave, Ph.D., Institut Pasteur, Unité de Défense Innée et Inflammation, F-75015, Paris, France. E-mail:

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