Lipocalins in Clinical Medicine

Lennart Lögdberg; Bo Åkerström

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Lipocalins in Clinical Medicine

Lennart Lögdberg and Bo Åkerström.

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This review highlights several possible future roles of lipocalins in human clinical medicine. Generically, due to their metabolism as low molecular weight plasma proteins, lipocalins are candidate markers of kidney functions. Clinical data strongly supporting this notion are available for α₁-microglobulin, retinol-binding protein, lipocalin prostaglandin D-synthase (also called “β-trace”), and neutrophil gelatinase-associated lipocalin (also called LCN2, siderocalin, and human neutrophil lipocalin). In addition, several lipocalins are acute phase reactants: α₁-acid glycoprotein (also called orosomucoid) and neutrophil gelatinase-associated lipocalin are particularly good markers of the acute phase response of inflammation. Finally, a group of xenogeneic lipocalins are under investigation for their possible roles in the diagnosis and treatment of allergy to animals.

Introduction

Human lipocalins have not yet won established places in clinical practice. However, an extensive literature now exists highlighting their possible roles as markers for a variety of diseases, notably in renal or inflammatory diseases (summarized in Table 1).¹^-⁵ Moreover, based on the biological activities of these molecules, individual lipocalins may have promise as therapeutic agents, e.g., for immunomodulation,⁶^,⁷ protection against oxidative stress (c.f., Chapter 10),⁸^-¹⁰ amelioration of acute ischemic renal injury,¹¹^,¹² or antimicrobial siderophore sequestration (c.f., Chapter 8).¹³^-¹⁵

Table 1

Lipocalins as diagnostic markers of pathological conditions.

Xenogeneic lipocalins, particularly from other mammals, but also from more divergent species, such as the Insecta members cockroach (B. germanica) and tick (A. reflexus), are potent allergens for atopic individuals (c.f., Chapter 15).¹⁶^,¹⁷ Thus, these lipocalins are likely to have clinical roles in future laboratory diagnostics (e.g., by serving as antigens for detecting specific IgE-antibodies in sera of allergic patients), as well as in clinical diagnostics (e.g., as antigen for prick-test or other provocation tests) and immunotherapy.

Markers for Assessing Renal Function and Disease

Markers Due to Renal Role in Metabolism of Low Molecular Weight Proteins

Members of the lipocalin superfamily are low molecular weight (LMW) proteins (˜20 kD) folded into a beta-sheet dominated (“beta-barrel”) structure.¹⁸ As such, they tend to be filtered relatively freely across the glomerular membrane into the primary urine.¹⁹ In the proximal tubules, they are reabsorbed by the tubular epithelial cells, and thus occur in the final urine in only minute amounts.¹⁹ The reabsorption of many members of this family has been demonstrated to be through an interaction with the endocytic receptor megalin, present on the luminal surface of the proximal tubules.²⁰^, ²¹

Due to this renal processing of LMW proteins, most lipocalins could be thought to serve as markers for both glomerular filtration rate (GFR) and proximal tubular function. Thus, their serum level tends to increase with reduced GFR, and lipocalins such as α₁-microglobulin (α₁m) and lipocalin prostaglandin D synthase (L-PGDS, β-trace) have been shown to be early and sensitive indicators of reduced GFR, and exhibit elevated levels already in the so called “creatinine-blind” range.²^,²²^-²⁴ Correspondingly, increased levels of LMW proteins, including lipocalins, are passed into the final urine in conditions of damage to the proximal tubules, such as occurs in poisoning by heavy metals (cadmium, lead, mercury, etc.).²^,³ Based on this principle, urinary β₂-microglobulin has long been a gold standard marker for tubular function.² However, other LMW proteins that are less sensitive to pH-variations or urinary density, such as α₁m (and perhaps other lipocalins) tend to perform as more consistent markers of tubular function.²^,²⁵

Urinary LMW protein levels are good markers for tubular function when GFR is normal. It should be noted that urinary levels of LMW proteins, including lipocalins, do increase in the absence of renal tubular dysfunction, in conditions of severely compromised GFR. Such poor GFR causes high serum levels, which is reflected in similarly high levels in the primary urine, exceeding the reabsorptive capacity in the proximal tubules.³ Thus, in such cases, LMW proteinuria does not indicate tubular dysfunction.

In evaluating proteinuria, urinary lipocalin quantitation can be combined with other quantitative and qualitative (test strip) analyte measurements to generate computer-aided diagnostic interpretations of high accuracy. Such a computer-based “urine protein expert system” including urinary α₁m levels has been used as a decision-making tool for distinguishing between prerenal, renal, and postrenal causes for the proteinuria and has been evaluated for multi-institutional use.²⁶^,²⁷

NGAL—A Specialized Role as Marker for Acute Renal Failure

Recently, the presence of the neutrophil gelatinase-associated lipocalin or NGAL (other names: Lipocalin 2, LCN2; Human neutrophil lipocalin, HNL) in serum or urine at 2h post cardiopulmonary bypass was demonstrated to be a powerful independent predictor of acute renal failure (ARF).²⁸ Renal ischemia-reperfusion injury is the leading cause of ARF, affecting up to 30-50% of patients in intensive care units, and it is associated with high mortality and morbidity.²⁸

NGAL does not only function as an early biomarker of acute ischemic renal injury, preceeding the increase in serum creatinine by 1-3 days; it also compares well with other recently proposed biomarkers for this condition.²⁸ This is most probably because increased NGAL levels are a consequence of two synergistic mechanisms: (1) reduced GFR and impaired proximal tubular function leading to accumulation of LMW proteins in serum and in urine, and (2) NGAL is induced by inflammatory stimuli, both generally and locally in the injured tubular epithelia.²⁹

Local NGAL-expression may reflect a homeostatic response to induce renal reepithelialization, as this lipocalin appears to regulate the in vitro epithelial morphogenesis of cultured renal tubular cells³⁰ and also may function as an iron-transporting mechanism in nephrogenesis.³¹ Consistent with these observations is the observed ameliorating effect of exogenously administered NGAL in a murine model of acute ischaemic renal injury.¹¹^,¹² Thus, in addition to being an impressive clinical marker, NGAL shows promise as a therapeutic tool in acute ischaemic renal failure.

Markers of Immunological/Inflammatory Activity

It has been noted that a subgroup of the lipocalins, denoted immunocalins and encompassing at least seven members encoded from the q32-34 region of human chromosome 9, exert a variety of immunomodulatory, anti-inflammatory, and anti-microbial effects and may be part of the innate immune system.⁴ These lipocalins include α₁-microglobulin, α₁-acid glycoprotein (AGP, orosomucoid), glycodelin (Gd, PP14), tear lipocalin (TL; Lipocalin 1, LCN1), NGAL, complement factor C8 γ-subunit (C8G), and L-PGDS.

Most, if not all, of these seven lipocalins are acute phase reactants, a sign that they may moderate harmful consequences of the inflammatory response, e.g., by exerting tissue protection during inflammation.⁴ AGP and NGAL are classical acute phase proteins and inflammatory stimuli lead to both enhanced transcription of the corresponding genes and a subsequent substantial elevation of serum concentrations of these proteins. The other five lipocalin genes can also be upregulated by proinflammatory cytokines, by microbial stimuli, or in selective conditions, such as pregnancy, but are not necessarily associated with generally elevated serum concentrations.⁴ They are nonetheless associated with a variety of protective functions.

Recent studies have illuminated the protective, anti-microbial properties of NGAL.¹⁴^,¹⁵^,³¹^-³³ Briefly, endotoxin (LPS) from gram-negative bacteria stimulates a 200-fold increase of NGAL-message and a 20-fold increase of the NGAL serum protein concentration in vivo.¹⁴

The liver appears to be the major source of NGAL. This activation is TLR4 (Toll-like receptor 4)-dependent, which implies an important function for NGAL in innate defense against bacterial infections.¹⁴

This defense mechanism of NGAL was recently disclosed. Bacteria, when growing in iron-restricted environments, such as serum, employ secreted siderophores (high-affinity, iron-sequestrating molecules) to compete for the available iron in their surrounding medium, which then enters the bacterium via receptors specific for iron-laden siderophores. It is thus intriguing that NGAL was found to specifically bind several catecholate-type siderophores, including enterochelin, with very high affinity.¹⁵ Enterochelin-like siderophores are made by a large number of human pathogenic bacteria.

Certain E. coli strains can be grown to exclusively depend on catecholate-type siderophorins during growth at iron-restricted conditions. NGAL is a particularly effective anti-microbial against such strains when NGAL is stoichiometrically in excess over enterochelin. Consistent with this, the in vivo growth of such bacteria is dramatically enhanced in NGAL knock-out mice compared to wild type mice.¹⁴ Thus, NGAL appears to be a powerful anti-microbial agent in iron-restricted environments and it acquired yet another name: siderocalin.¹⁵

Additional research has demonstrated that NGAL also binds soluble siderophores of mycobacteria, such as carboxymycobactins of M. tuberculosis, via a degenerate recognition mechanism. ³³ TL, another lipocalin, also appears to exert anti-microbial effects via siderophore sequestration.¹³ Its siderophore binding is less specific and of lower affinity than NGAL, and includes binding to bacterial siderophores, such as catecholate-type enterobactin and hydroxymate-type desferrioxamin, as well as to all major classes of fungal siderophores.

The inflammatory and immunomodulating properties of AGP, as well as the importance of its glycosylation pattern, were recently reviewed.⁵ Increasing interest has focussed on inflammation-sensitive proteins, such as AGP, whose elevated levels in plasma or urine are associated with increased cardiovascular and overall mortality in patients with other risk factors.³⁴^,³⁵

Markers in Oncology

The potential role of lipocalins as markers for malignancy was reviewed recently.³⁶ The known role of lipocalin ligands in cell differentiation and proliferation, and the protease-inhibitory properties of some lipocalins, suggested several pathways for interaction between lipocalins and cancer cells.

Since then, it has been demonstrated that AGP is an independent predictor of treatment response and a prognostic factor for survival in patients with non-small cell lung cancer and docetaxel chemotherapy.³⁷ In contrast, a high degree of fucosylation of AGP is associated with poor prognosis in patients with advanced malignancies.³⁸ More recently, NGAL was shown to reverse the malignant phenotype of Ras-transformed cells.³⁹ When added as purified NGAL or as NGAL vectors to Ras-transformed 4T1 mouse mammary tumor cells, invasiveness and metastasis were diminished.

Since the liver is the major site of synthesis of many lipocalins,these proteins may be useful as markers for hepatocyte origin and activity. Thus, elevated plasma levels of α₁m have been reported in patients with hepatocellular carcinoma (HCC).⁴⁰ Similarly, it has been suggested that the immunohistochemical demonstration of α₁m on liver sections may help distinguish between primary liver tumors vs metastases.⁴¹

Markers for the Diagnosis of Allergy and Possible Therapeutic Tools for Immunotherapy

Immunoglobulin E-mediated allergy to environmental antigens (present in pollen, dust, animal dander, food, etc) is an important and costly health problem in the industrialized world and its incidence/prevalence is increasing.⁴²^-⁴⁵ A subset of allergies usually linked to respiratory sensitization includes hypersensitivity to other mammals such as pets, farm animals, research animals, and their wild counterparts. Intriguingly, recent research has demonstrated that the major mammalian allergens tend to belong to the lipocalin superfamily (c.f., Chapter 15).¹⁷

This phenomenon likely reflects the functional properties of the lipocalin molecules such as their ligand binding and receptor interactions, and may also represent the intricate interplay between such lipocalin allergens and their endogenous human orthologues in the patients. Further research on the etiology and pathophysiology of lipocalin allergy may, therefore, reveal fundamental aspects of the normal physiology of IgE responses and of mast cell biology.

However, of immediate clinical importance is that the research identifying and characterizing lipocalin allergens has generated a new panel of purified, well-characterized natural and recombinant allergens. These are being made available gradually for the diagnosis and treatment of allergy⁴⁶ through the establishment of more sensitive detection assays for anti-lipocalin IgEs⁴⁷^,⁴⁸ and the biological diagnosis in prick assays.⁴⁹ With time, this is likely to be generalized to the use of purified natural and/or recombinant lipocalin allergens in diagnostic microarrays,⁵⁰ for various patient provocation testing methods,⁵¹ and for devising innovative immunotherapy protocols.⁵²^-⁵⁴

Concluding Remarks

Lipocalins are now positioned to find clinical roles as biomarkers for renal function, for inflammation, and for allergy diagnosis. The critical function of some lipocalins in selected pathological conditions further suggest that the future may witness the development of lipocalin-based therapeutic agents.

Acknowledgements

We thank Linda Lögdberg, PhD, for revising the english text.

References

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Lögdberg L, Åkerström B. Lipocalins in Clinical Medicine. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

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Introduction
Markers for Assessing Renal Function and Disease
Markers of Immunological/Inflammatory Activity
Markers in Oncology
Markers for the Diagnosis of Allergy and Possible Therapeutic Tools for Immunotherapy
Concluding Remarks
Acknowledgements
References

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Madame Curie Bioscience Database [Internet].

Lipocalins in Clinical Medicine

Authors

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Introduction

Table 1

Markers for Assessing Renal Function and Disease

Markers Due to Renal Role in Metabolism of Low Molecular Weight Proteins

NGAL—A Specialized Role as Marker for Acute Renal Failure

Markers of Immunological/Inflammatory Activity

Markers in Oncology

Markers for the Diagnosis of Allergy and Possible Therapeutic Tools for Immunotherapy

Concluding Remarks

Acknowledgements

References

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