Differential Regulation of the Nature and Functions of Dendritic Cells and Macrophages by Cathepsin E

Kakehashi, Hiroe; Nishioku, Tsuyoshi; Tsukuba, Takayuki; Kadowaki, Tomoko; Nakamura, Seiji; Yamamoto, Kazuo

doi:10.4049/jimmunol.179.9.5728

Cited by 36 publications

(43 citation statements)

References 56 publications

(57 reference statements)

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“…However, contrasting results were seen when macrophages and DC were compared, as cathepsin E null DC showed an enhanced presentation of ovalbumin, a result attributed to increased phagocytosis and elevated expression of co-stimulatory molecules [31]. Cathepsin E-deficient mice are susceptible to developing atopic dermatitis, attributed to the accumulation of both Th2 polarising cytokines and IgE.…”

Section: Antigen Processing and Presentationmentioning

confidence: 97%

“…Loss or inhibition of cathepsin E has been reported to compromise processing and presentation of antigens such as ovalbumin, myoglobin and tetanus toxin [31,32]. However, contrasting results were seen when macrophages and DC were compared, as cathepsin E null DC showed an enhanced presentation of ovalbumin, a result attributed to increased phagocytosis and elevated expression of co-stimulatory molecules [31].…”

Section: Antigen Processing and Presentationmentioning

confidence: 99%

“…Individual enzymes present in lysosomal extracts frequently dominate processing of specific antigens in vitro and blockade of those enzymes can reduce presentation of T-cell epitopes [27,28]. This requirement may be for initial ''unlocking'' cleavages [29, 30] or downstream processing events [28].Loss or inhibition of cathepsin E has been reported to compromise processing and presentation of antigens such as ovalbumin, myoglobin and tetanus toxin [31,32]. However, contrasting results were seen when macrophages and DC were compared, as cathepsin E null DC showed an enhanced presentation of ovalbumin, a result attributed to increased phagocytosis and elevated expression of co-stimulatory molecules [31].…”

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Diverse regulatory roles for lysosomal proteases in the immune response

et al. 2009

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The innate and adaptive immune system utilise endocytic protease activity to promote functional immune responses. Cysteine and aspartic proteases (cathepsins) constitute a subset of endocytic proteases, the immune function of which has been described extensively. Although historically these studies have focused on their role in processes such as antigen presentation and zymogen processing within the endocytic compartment, recent discoveries have demonstrated a critical role for these proteases in other intracellular compartments, and within the extracellular milieu. It has also become clear that their pattern of expression and substrate specificities are more diverse than was first envisaged. Here, we discuss recent advances addressing the role of lysosomal proteases in various aspects of the immune response. We pay attention to reports demonstrating cathepsin activity outside of its canonical endosome/lysosome microenvironment.Key words: Cathepsins . Endosomes . Immune regulation . Lysosomes IntroductionThe endosome/lysosome compartments, together with the cytosolic proteasomes, are the two major protein degradation systems in cells. Both have emerged as having many important regulatory functions in addition to their role in protein breakdown for amino acid recycling. For example, limited proteolysis within the endocytic pathway can induce activating conformational changes [1,2], release functional proteins from chaperones [3], and cleave soluble bioactive molecules from membrane-anchored precursors [4]. The concept of ''regulation through limited destruction'' is evident in many processes in innate and adaptive immunity. Endosome/lysosome-located proteases play key roles in antigen processing and presentation, cytokine regulation, NKT cell development, activation of serine protease zymogens in regulated secretory granules, integrin activation, induction of apoptosis and TLR signalling. Given that these processes may also be associated with undesirable immune responses and inflammation, the proteases involved may be considered as attractive drug targets. EnzymesEndosomes and lysosomes harbour mainly cysteine and aspartic acid proteases so-named because their active site utilises either a cysteine thiol or an aspartic acid as a key part of the catalytic site. Some endosome/lysosome located serine proteases such as cathepsin G, granzymes and thymus specific serine protease (TSSP) have important roles in the immune system; however, we focus primarily here on the cysteine and aspartic proteases. Most of the lysosomal cysteine proteases are related to papain and belong to the so-called C1 family. These include cathepsins L, S, C, F, H, B, X, K, V and W. Cathepsins D and E are also found in lysosomes but are aspartic acid proteases related to pepsin. An additional cysteine protease is found in lysosomes, which is more closely related to the caspases. This is asparaginyl endopeptidase (AEP) or legumain, a member of the C13 family. Some of these enzymes are endopeptidases (cathepsins S, L, K, F, V, D, E and AEP), where...

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Section: Antigen Processing and Presentationmentioning

confidence: 97%

Section: Antigen Processing and Presentationmentioning

confidence: 99%

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confidence: 99%

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Diverse regulatory roles for lysosomal proteases in the immune response

et al. 2009

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“…Cathepsin E is predominantly found in immune-related cells, including macrophages, dendritic cells, and microglia [3,4] or in the epithelial cells of the gastrointestinal mucosa and skin [5,6]. To investigate the physiological or pathological roles of the proteinase in vivo, we have previously generated cathepsin E-deficient (CatE -/-) mice.…”

Section: Introductionmentioning

confidence: 99%

Defective adipose tissue development associated with hepatomegaly in cathepsin E-deficient mice fed a high-fat diet

Kadowaki

Kido

Hatakeyama

et al. 2014

Biochemical and Biophysical Research Communications

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Running title: Fat-induced cathepsin E-deficient mice Key words: cathepsin E, high-fat diet, adipose tissue AbstractCathepsin E is an intracellular aspartic proteinase, which is predominantly distributed in immune-related and epithelial cells. However, the role of the enzyme in adipose tissues remains unknown. In this study, we investigated the characteristics of cathepsin E-deficient (CatE -/-) mice fed a high-fat diet (HFD), as a mouse model of obesity. HFD-fed CatE -/-mice displayed reduced body weight gain and defective development of white adipose tissue (WAT) and brown adipose tissue (BAT), compared with HFD-fed wild-type mice. Moreover, fat-induced CatE -/-mice showed abnormal lipid accumulation in non-adipose tissues characterized by hepatomegaly, which is probably due to defective adipose tissue development. Detailed pathological and biochemical analyses showed that hepatomegaly was accompanied by hepatic steatosis and hypercholesterolemia in HFD-induced CatE -/-mice. In fat-induced CatE -/-mice, the number of macrophages infiltrating into WAT was significantly lower than in fat-induced wild-type mice. Thus, the impaired adipose tissue development in HFD-induced CatE -/-mice was probably due to reduced infiltration of macrophages and may lead to hepatomegaly accompanied by hepatic steatosis and hypercholesterolemia.

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“…The chemotactic receptors belong to the 7-transmembrane-G-protein-coupled receptor family, and trigger various immune responses besides chemotaxis, induce the production of reactive oxygen species, and stimulate the release of proteolytic enzymes from granules, in the case of neutrophils (17). Concerning chemotactic responses, we have more recently reported that bone-marrow derived macrophages from CatE -/-mice display impaired chemotaxis in responses to a chemokine and a bacterial peptide (18).…”

Section: Introductionmentioning

confidence: 99%

Impaired chemotaxis and cell adhesion due to decrease in several cell-surface receptors in cathepsin E-deficient macrophages

Tsukuba

Yanagawa

Okamoto

et al. 2009

Journal of Biochemistry

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SUMMARYCathepsin E is an endo-lysosomal aspartic proteinase exclusively present in immune system cells. Previous studies have shown that cathepsin E-deficient (CatE -/-) mice display aberrant immune responses such as atopic dermatitis and higher susceptibility to bacterial infection.However, the mechanisms underlying abnormal immune responses induced by cathepsin E deficiency are still unclear. In this study, we found that the cell-surface levels of chemotactic 3

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Differential Regulation of the Nature and Functions of Dendritic Cells and Macrophages by Cathepsin E

Cited by 36 publications

References 56 publications

Diverse regulatory roles for lysosomal proteases in the immune response

Diverse regulatory roles for lysosomal proteases in the immune response

Defective adipose tissue development associated with hepatomegaly in cathepsin E-deficient mice fed a high-fat diet

Impaired chemotaxis and cell adhesion due to decrease in several cell-surface receptors in cathepsin E-deficient macrophages

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