Lactoferrin Is an Allosteric Enhancer of the Proteolytic Activity of Cathepsin G

Eipper, Steffen; Steiner, Robin; Lesner, Adam; Sieńczyk, Marcin; Palesch, David; Halatsch, Marc Eric; Zaczyńska, Ewa; Heim, Christopher; Hartmann, M.D.; Zimecki, Michał; Wirtz, Christian Rainer; Burster, Timo

doi:10.1371/journal.pone.0151509

Cited by 24 publications

(31 citation statements)

References 41 publications

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“…According to the recent report, we demonstrate the augmentation of the enzymatic activity of CatG by LF [17]. Here, the results precisely indicate an enhancing effect of LF to CatG in upregulation of MHC I at the cell surface of PBMCs.…”

Section: Discussionsupporting

confidence: 85%

Exogenous cathepsin G upregulates cell surface MHC class I molecules on immune and glioblastoma cells

et al. 2016

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Major histocompatibility complex (MHC) class I molecules present antigenic peptides to cytotoxic T cells. During an adaptive immune response, MHC molecules are regulated by several mechanisms including lipopolysaccharide (LPS) and interferon gamma (IFN-g). However, it is unclear whether the serine protease cathepsin G (CatG), which is generally secreted by neutrophils at the site of inflammation, might regulate MHC I molecules. We identified CatG, and to a higher extend CatG and lactoferrin (LF), as an exogenous regulator of cell surface MHC I expression of immune cells and glioblastoma stem cells. In addition, levels of MHC I molecules are reduced on dendritic cells from CatG deficient mice compared to their wild type counterparts. Furthermore, cell surface CatG on immune cells, including T cells, B cells, and NK cells triggers MHC I on THP-1 monocytes suggesting a novel mechanism for CatG to facilitate intercellular communication between infiltrating cells and the respective target cell. Subsequently, our findings highlight the pivotal role of CatG as a checkpoint protease which might force target cells to display their intracellular MHC I:antigen repertoire.

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Section: Discussionsupporting

confidence: 85%

Exogenous cathepsin G upregulates cell surface MHC class I molecules on immune and glioblastoma cells

et al. 2016

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“…Lactoferrin also modulates adaptive immune responses by accelerating the maturation of T-cell precursors into competent CD4 ϩ T helper cells (154) and enhances the differentiation of immature B cells into antigen-presenting cells (155). Following neutrophil activation, lactoferrin released from specific granules enhances the activation of cathepsin G and serine proteases, thereby promoting innate immune responses during acute inflammation (156,157).…”

Section: Granulopoiesismentioning

confidence: 99%

The Ontogeny of a Neutrophil: Mechanisms of Granulopoiesis and Homeostasis

Lawrence

Corriden

Nizet

2018

Microbiol Mol Biol Rev

177

173

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Comprising the majority of leukocytes in humans, neutrophils are the first immune cells to respond to inflammatory or infectious etiologies and are crucial participants in the proper functioning of both innate and adaptive immune responses. From their initial appearance in the liver, thymus, and spleen at around the eighth week of human gestation to their generation in large numbers in the bone marrow at the end of term gestation, the differentiation of the pluripotent hematopoietic stem cell into a mature, segmented neutrophil is a highly controlled process where the transcriptional regulators C/EBP-α and C/EBP-ε play a vital role. Recent advances in neutrophil biology have clarified the life cycle of these cells and revealed striking differences between neonatal and adult neutrophils based on fetal maturation and environmental factors. Here we detail neutrophil ontogeny, granulopoiesis, and neutrophil homeostasis and highlight important differences between neonatal and adult neutrophil populations.

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“…Neutrophils directly produce LTF, which upon release plays a pivotal role in the development and resolution of inflammation. LTF also increases the activity of cathepsin G, a known antibacterial enzyme ( 66 ), and broadens its substrate specificity ( 67 ), suggesting that LTF acts in concert with antibacterial neutrophil-derived enzymes in the initial phase of infection. However, it should be noted that there is a relative feedback loop; LTF released from neutrophils can effectively reduce neutrophil extracellular traps, important in overall inflammatory response ( 11 ).…”

Section: Inflammation: An Immune Response To Injurymentioning

confidence: 99%

Lactoferrin in a Context of Inflammation-Induced Pathology

2017

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Much progress has been achieved to elucidate the function of lactoferrin (LTF), an iron-binding glycoprotein, in the milieu of immune functionality. This review represents a unique examination of LTF toward its importance in physiologic homeostasis as related to development of disease-associated pathology. The immunomodulatory nature of this protein derives from its unique ability to “sense” the immune activation status of an organism and act accordingly. Underlying mechanisms are proposed whereby LTF controls disease states, thereby pinpointing regions of entry for LTF in maintenance of various physiological pathways to limit the magnitude of tissue damage. LTF is examined as a first line mediator in immune defense and response to pathogenic and non-pathogenic injury, as well as a molecule critical for control of oxidative cell function. Mechanisms of interaction of LTF with its receptors are examined, with a focus on protective effects via regulation of enzyme activities and reactive oxygen species production, immune deviation, and prevention of cell apoptosis. Indeed, LTF serves as a critical control point in physiologic homeostasis, functioning as a sensor of immunological performance related to pathology. Specific mediation of tissue pathophysiology is described for maintenance of intestinal integrity during endotoxemia, elicited airway inflammation due to allergens, and pulmonary damage during tuberculosis. Finally, the role of LTF to alter differentiation of adaptive immune function is examined, with specific recognition of its utility as a vaccine adjuvant to control subsequent lymphocytic reactivity. Overall, it is clear that while the ability of LTF to both sequester iron and to direct reactive oxygen intermediates is a major factor in lessening damage due to excessive inflammatory responses, further effects are apparent through direct control over development of higher order immune functions that regulate pathology due to insult and injury. This culminates in attenuation of pathological damage during inflammatory injury.

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Lactoferrin Is an Allosteric Enhancer of the Proteolytic Activity of Cathepsin G

Cited by 24 publications

References 41 publications

Exogenous cathepsin G upregulates cell surface MHC class I molecules on immune and glioblastoma cells

Exogenous cathepsin G upregulates cell surface MHC class I molecules on immune and glioblastoma cells

The Ontogeny of a Neutrophil: Mechanisms of Granulopoiesis and Homeostasis

Lactoferrin in a Context of Inflammation-Induced Pathology

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