Cathepsins B, L and D in inflammatory bowel disease macrophages and potential therapeutic effects of cathepsin inhibition <i>in vivo</i>

Menzel, K.; Hausmann, Martin; Obermeier, Florian; Schreiter, K.; Dunger, Nadja; Bataille, Frauke; Falk, Werner; Schölmerich, Jürgen; Herfarth, Hans H; Rogler, Gerhard

doi:10.1111/j.1365-2249.2006.03188.x

Cited by 106 publications

(91 citation statements)

References 30 publications

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“…Interestingly, expression of both cathepsin S and B has been well documented at inflammatory sites in various disease models including pancreatitis (39), inflammatory bowel disease (40), and atherosclerosis (41). It seems plausible that cathepsin-mediated cleavage of Rip1 kinase could play a role in perpetuating macrophage survival and function within inflammatory sites.…”

Section: Discussionmentioning

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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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: Discussionmentioning

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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“…It has been shown earlier that expression of tissue-degrading cathepsins B, L, and D may play an important role in the pathophysiology of IBD and that they can provide a new target for IBD therapy. 20 We can speculate that large amounts of Cat-G may be released from neutrophils into tissues but also into the colonic lumen consecutively to epithelial barrier disruption. Interestingly, anti-neutrophil cytoplasmic antibodies targeting Cat-G are found in the sera of more than half of UC patients.…”

Section: Discussionmentioning

confidence: 99%

Luminal Cathepsin G and Protease-Activated Receptor 4

Dabek

Ferrier

Róka

et al. 2009

The American Journal of Pathology

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Impairment of the colonic epithelial barrier and neutrophil infiltration are common features of inflammatory bowel disease. Luminal proteases affect colonic permeability through protease-activated receptors (PARs). We evaluated: (i) whether fecal supernatants from patients with ulcerative colitis (UC) trigger alterations of colonic paracellular permeability and inflammation, and (ii) the roles of cathepsin G (Cat-G), a neutrophil serine protease, and its selective receptor, PAR 4 , in these processes. Expression levels of both PAR 4 and Cat-G were determined in colonic biopsies from UC and healthy subjects. The effects of UC fecal supernatants on colonic paracellular permeability were measured in murine colonic strips. Involvement of Cat-G and PAR 4 was evaluated using pepducin P4pal-10 and specific Cat-G inhibitor (SCGI), respectively. In addition, the effect of PAR 4 -activating peptide was assessed. UC fecal supernatants, either untreated or pretreated with SCGI, were infused into mice, and myeloperoxidase activity was determined. PAR 4 was found to be overexpressed in UC colonic biopsies. Increased colonic paracellular permeability that was triggered by UC fecal supernatants was blocked by both SCGI (77%) and P4pal-10 (85%). Intracolonic infusion of UC fecal supernatants into mice increased myeloperoxidase activity. This effect was abolished by SCGI. These observations support that both Cat-G and PAR 4 play key roles in generating and/or amplifying relapses in UC and provide a rationale for the development of new therapeutic agents in the treatment of this disease.

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“…Instead, CatL-positive cells (primarily immunocytes) were accumulated in the stromal compartment of the colon during all stages of chronic colitis ( Figure 1G). It has been previously shown that CatL plays an important pathophysiological role in colonic inflammation and that macrophages are the primary cellular source of inducible CatL expression in inflamed colon of UC patients and in acute DSS-induced mouse colitis (62). A different cellular source of heparanase (epithelial) and CatL (stroma/immunocytes) implies that proteolytic processing of heparanase by CatL takes place in the extracellular space.…”

Section: Macrophages Represent Both Cellular Targets For Heparanase Amentioning

confidence: 99%

Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis in mice

Lerner

Hermano²,

Zcharia³

et al. 2011

J. Clin. Invest.

171

295

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Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is closely associated with colon cancer. Expression of the enzyme heparanase is clearly linked to colon carcinoma progression, but its role in UC is unknown. Here we demonstrate for what we believe to be the first time the importance of heparanase in sustaining the immune-epithelial crosstalk underlying colitis-associated tumorigenesis. Using histological specimens from UC patients and a mouse model of dextran sodium sulfate-induced colitis, we found that heparanase was constantly overexpressed and activated throughout the disease. We demonstrate, using heparanase-overexpressing transgenic mice, that heparanase overexpression markedly increased the incidence and severity of colitis-associated colonic tumors. We found that highly coordinated interactions between the epithelial compartment (contributing heparanase) and mucosal macrophages preserved chronic inflammatory conditions and created a tumor-promoting microenvironment characterized by enhanced NF-κB signaling and induction of STAT3. Our results indicate that heparanase generates a vicious cycle that powers colitis and the associated tumorigenesis: heparanase, acting synergistically with the intestinal flora, stimulates macrophage activation, while macrophages induce production (via TNF-α-dependent mechanisms) and activation (via secretion of cathepsin L) of heparanase contributed by the colon epithelium. Thus, disruption of the heparanase-driven chronic inflammatory circuit is highly relevant to the design of therapeutic interventions in colitis and the associated cancer.

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Cathepsins B, L and D in inflammatory bowel disease macrophages and potential therapeutic effects of cathepsin inhibition in vivo

Cited by 106 publications

References 30 publications

Cathepsins Limit Macrophage Necroptosis through Cleavage of Rip1 Kinase

Cathepsins Limit Macrophage Necroptosis through Cleavage of Rip1 Kinase

Luminal Cathepsin G and Protease-Activated Receptor 4

Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis in mice

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