Modulation of the Endosomal and Lysosomal Distribution of Cathepsins B, L and S in Human Monocytes/Macrophages

Schmid, Heide; Sauerbrei, Ramona; Schwarz, Gerold; Weber, Ekkehard; Kalbacher, Hubert

doi:10.1515/bc.2002.143

Cited by 19 publications

(18 citation statements)

References 34 publications

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“…To further confirm the role of cathepsins in the cleavage of Rip1, we used siRNA knockdown approach to target two key cysteine family cathepsins, which are highly expressed within macrophages (19). Consistent with a role in the cleavage of Rip1, knockdown of either cathepsin S or cathepsin B resulted in less cleavage of Rip1 kinase (Fig.…”

Section: The Journal Of Immunology 5673mentioning

confidence: 79%

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Cathepsins Limit Macrophage Necroptosis through Cleavage of Rip1 Kinase

McComb

Shutinoski

Thurston

et al. 2014

The Journal of Immunology

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It has recently been shown that programmed necrosis, necroptosis, may play a key role in the development of inflammation. Deciphering the regulation of this pathway within immune cells may therefore have implications in pathology associated with inflammatory diseases. We show that treatment of macrophages with the pan caspase inhibitor (zVAD-FMK) results in both increased phosphorylation and decreased cleavage of receptor interacting protein kinase-1 (Rip1), leading to necroptosis that is dependent on autocrine TNF signaling. Stimulation of cells with TLR agonists such as LPS in the presence of zVAD-FMK also induced Rip1-phosphorylation via a TNFR-independent mechanism. Further examination of Rip1 expression under these stimulatory conditions revealed a regulatory cleavage of Rip1 in macrophages that is not apparently attributable to caspase-8. Instead, we provide novel evidence that cysteine family cathepsins, which are highly abundant in myeloid cells, can also cleave Rip1 kinase. Using small interfering RNA knockdown, specific cathepsin inhibitors, and cell-free cleavage assays, we demonstrate that cysteine cathepsins B and S can directly cleave Rip1. Finally, we demonstrate that only through combined inhibition of cathepsins and caspase-8 could a potent induction of macrophage necroptosis be achieved. These data reveal a novel mechanism of regulation of necroptosis by cathepsins within macrophage cells.

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Section: The Journal Of Immunology 5673mentioning

confidence: 79%

“…Thus, we provide novel insight into the proteolytic control of the key necroptotic kinase, Rip1. Given the ability of macrophages to modulate expression and localization of cathepsins in response to inflammatory stimuli (19,20), this may represent an important means of controlling necrotic cell death during an immune response.…”

mentioning

confidence: 99%

Cathepsins Limit Macrophage Necroptosis through Cleavage of Rip1 Kinase

McComb

Shutinoski

Thurston

et al. 2014

The Journal of Immunology

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“…act. is observed in endosomal, but not in lysosomal, fractions (41). In addition, both cathepsins are expressed in HEK293 and THP-1 cells, whereas cathepsin S is expressed in THP-1 cells but not in HEK293 cells (K. Iwano, A. Watanabe, and M. Matsumoto, unpublished data).…”

Section: Discussionmentioning

confidence: 95%

Endosomal Localization of TLR8 Confers Distinctive Proteolytic Processing on Human Myeloid Cells

Ishii

Funami

Tatematsu

et al. 2014

The Journal of Immunology

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Nucleic acid–sensing TLRs are involved in both antimicrobial immune responses and autoimmune inflammation. TLR8 is phylogenetically and structurally related to TLR7 and TLR9, which undergo proteolytic processing in the endolysosomes to generate functional receptors. Recent structural analyses of human TLR8 ectodomain and its liganded form demonstrated that TLR8 is also cleaved, and both the N- and C-terminal halves contribute to ligand binding. However, the structures and ssRNA recognition mode of endogenous TLR8 in human primary cells are largely unknown. In this study, we show that proteolytic processing of TLR8 occurs in human monocytes and macrophages in a different manner compared with TLR7/9 cleavage. The insertion loop between leucine-rich repeats 14 and 15 in TLR8 is indispensable for the cleavage and stepwise processing that occurs in the N-terminal fragment. Both furin-like proprotein convertase and cathepsins contribute to TLR8 cleavage in the early/late endosomes. TLR8 recognizes viral ssRNA and endogenous RNA, such as microRNAs, resulting in the production of proinflammatory cytokines. Hence, localization sites of the receptors are crucial for the nucleic acid–sensing mode and downstream signaling.

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“…This feature of retaining antigen for presentation later, after appropriate maturation, is a characteristic that has been ascribed mainly to DCs and is thought to distinguish them from macrophages [39], which have little capacity to retain antigens for delayed presentation. Monocytes may be less proteolytic than macrophages [40], allowing for retention rather than degradation of antigens.…”

Section: Monocytes Can Acquire Exogenous Antigens In the Bone Marrow mentioning

confidence: 99%

Antigen presentation by monocytes and monocyte-derived cells

Randolph

Jakubzick

2008

Current Opinion in Immunology

200

177

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SummaryMonocytes are circulating mononuclear phagocytes with a fundamental capacity to differentiate into macrophages. This differentiation can, in the presence of the right environmental cues, be re-directed instead to dendritic cells (DCs). Recent advances have been made in understanding the role of monocytes and their derivatives in presenting antigen to drive immune responses, and we review this topic herein. We briefly discuss the heterogeneity of monocytes in the blood and subsequently raise the possibility that one of the major monocyte phenotypes in the blood corresponds with a population of "blood DCs" previously proposed to drive T-independent antibody reactions in the spleen. Then we evaluate the role of monocytes in T-dependent immunity, considering their role in acquiring antigens for presentation prior to exiting the bloodstream and their ability to differentiate into macrophages versus antigen-presenting DCs. Finally, we review recent literature on the role of monocyte-derived cells in cross-presentation and discuss the possibility that monocyte-derived cells participate critically in processing antigen for cross-priming, even if they do not present that antigen to T cells themselves.Just recently, we participated in a group discussion with other colleagues whose research interests includes the biology of monocytes, and the discussion moved to the point of whether one can define the term "monocyte." Not all of our colleagues believed that such a definition could be clearly made in the current molecular age where cell types are readily divided up and defined by the presence and absence of an array of cell surface markers. However, we cannot approach research on the subject of monocytes without drawing a definition for these cells. Though universal agreement on this definition may not be possible, as we learned during this recent collegial exchange, the definition we adhere to is practical and a product of our training and discussion with other experts on monocytes over more than 15 years. For decades, a monocyte was identifiable morphologically and functionally as the mononuclear phagocyte in the blood [1][2][3]. Corresponding with this definition was the understanding that the cell readily differentiated into macrophages. Thus, our research on monocytes operates under the premise that monocytes are (a) mononuclear cells in the circulation with (b) the capacity for phagocytosis and (c) propensity to differentiate to macrophages at least in some settings. Some cell types, often termed circulating dendritic cells (DCs), have been identified in human blood that fit one or both of the first two parts of the definition but so far not the third [4][5][6]. So, fittingly, these latter cells are not included in the definition of monocytes. We also uphold the view that the term "monocyte" defines a cell that is in the bloodstream. Once a monocyte extravasates into tissue, a differentiation program toward macrophages or DCs begins, and the cell should no longer be referred to as a monocyte, but rather as a mo...

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Modulation of the Endosomal and Lysosomal Distribution of Cathepsins B, L and S in Human Monocytes/Macrophages

Cited by 19 publications

References 34 publications

Cathepsins Limit Macrophage Necroptosis through Cleavage of Rip1 Kinase

Cathepsins Limit Macrophage Necroptosis through Cleavage of Rip1 Kinase

Endosomal Localization of TLR8 Confers Distinctive Proteolytic Processing on Human Myeloid Cells

Antigen presentation by monocytes and monocyte-derived cells

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