Up-regulated cathepsin C induces macrophage M1 polarization through FAK-triggered p38 MAPK/NF-κB pathway

Alam, Shahid; Liu, Qing; Liu, Shuang; Liu, Yanna; Yang, Xin; Liu, Gang; Fan, Kai; Ma, Jin

doi:10.1016/j.yexcr.2019.06.017

Cited by 46 publications

(41 citation statements)

References 37 publications

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“…Another cathepsin family member warranting investigation in this context is cathepsin C. Strong expression of cathepsin C was detected in murine M1 macrophages and seems to be important for M1 polarization status. Cathepsin C activity was reported to be associated with pro-inflammatory activation of the focal adhesion kinase (FAK) and p38MAPK/NFκB signaling [87].…”

Section: Discussionmentioning

confidence: 99%

Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages

Oelschlaegel

Sadan

Salpeter

et al. 2020

Cancers

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Stroma-infiltrating immune cells, such as tumor-associated macrophages (TAM), play an important role in regulating tumor progression and chemoresistance. These effects are mostly conveyed by secreted mediators, among them several cathepsin proteases. In addition, increasing evidence suggests that stroma-infiltrating immune cells are able to induce profound metabolic changes within the tumor microenvironment. In this study, we aimed to characterize the impact of cathepsins in maintaining the TAM phenotype in more detail. For this purpose, we investigated the molecular effects of pharmacological cathepsin inhibition on the viability and polarization of human primary macrophages as well as its metabolic consequences. Pharmacological inhibition of cathepsins B, L, and S using a novel inhibitor, GB111-NH2, led to changes in cellular recycling processes characterized by an increased expression of autophagy- and lysosome-associated marker genes and reduced adenosine triphosphate (ATP) content. Decreased cathepsin activity in primary macrophages further led to distinct changes in fatty acid metabolites associated with increased expression of key modulators of fatty acid metabolism, such as fatty acid synthase (FASN) and acid ceramidase (ASAH1). The altered fatty acid profile was associated with an increased synthesis of the pro-inflammatory prostaglandin PGE2, which correlated with the upregulation of numerous NFkB-dependent pro-inflammatory mediators, including interleukin-1 (IL-1), interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2), and tumor necrosis factor-alpha (TNFα). Our data indicate a novel link between cathepsin activity and metabolic reprogramming in macrophages, demonstrated by a profound impact on autophagy and fatty acid metabolism, which facilitates a pro-inflammatory micromilieu generally associated with enhanced tumor elimination. These results provide a strong rationale for therapeutic cathepsin inhibition to overcome the tumor-promoting effects of the immune-evasive tumor micromilieu.

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Section: Discussionmentioning

confidence: 99%

Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages

Oelschlaegel

Sadan

Salpeter

et al. 2020

Cancers

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“…Aminodipeptidase + (Alam et al, 2019) Cathepsin F Endopeptidase + (Shi et al, 2000) Cathepsin H Aminopeptidase, Endopeptidase + (Woischnik et al, 2008) Cathepsin K (O2)…”

Section: Cysteinementioning

confidence: 99%

“…In macrophages, Cts D expression is highly differentiation-dependent and was shown to be increased upon maturation of monocytes into macrophages (Sintiprungrat et al, 2010). Macrophages also show the expression of cysteine cathepsins that appear ubiquitously in human cells, including Cts B (Rodriguez-Franco et al, 2012), C (also known as Cts J, dipeptidyl peptidase I or DPPI) (Alam et al, 2019), F (Shi et al, 2000), H (Woischnik et al, 2008) and L (Beers et al, 2003). However, their abundance, with the exception of Cts F, often increases in activated cells (Reddy et al, 1995;Pires et al, 2016).…”

Section: Endopeptidasementioning

confidence: 99%

“…For example, Ctsc is up-and down-regulated in M1 and M2 macrophages, respectively, whereas its deficiency leads to combined M2 (in vitro) and Th2 (in vivo) polarization (Herıás et al, 2015). Treatment of macrophages with an active monomer of Cts C facilitates their polarization toward M1 phenotype through focal adhesion kinase (FAK)-induced p38 mitogen-activated protein kinase (MAPK)/nuclear factor (NF)-kB signaling pathway activation (Alam et al, 2019). Apparently, gut macrophages can be polarized toward M2 phenotype by Cts K secreted through the toll-like receptor (TLR)4 signaling initiated by gutmicrobiota (Li et al, 2019).…”

Section: Endopeptidasementioning

confidence: 99%

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Cathepsins in Bacteria-Macrophage Interaction: Defenders or Victims of Circumstance?

Szulc-Dąbrowska

Bossowska-Nowicka

Struzik

et al. 2020

Front. Cell. Infect. Microbiol.

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Macrophages are the first encounters of invading bacteria and are responsible for engulfing and digesting pathogens through phagocytosis leading to initiation of the innate inflammatory response. Intracellular digestion occurs through a close relationship between phagocytic/endocytic and lysosomal pathways, in which proteolytic enzymes, such as cathepsins, are involved. The presence of cathepsins in the endo-lysosomal compartment permits direct interaction with and killing of bacteria, and may contribute to processing of bacterial antigens for presentation, an event necessary for the induction of antibacterial adaptive immune response. Therefore, it is not surprising that bacteria can control the expression and proteolytic activity of cathepsins, including their inhibitors – cystatins, to favor their own intracellular survival in macrophages. In this review, we summarize recent developments in defining the role of cathepsins in bacteria-macrophage interaction and describe important strategies engaged by bacteria to manipulate cathepsin expression and activity in macrophages. Particularly, we focus on specific bacterial species due to their clinical relevance to humans and animal health, i.e., Mycobacterium, Mycoplasma, Staphylococcus, Streptococcus, Salmonella, Shigella, Francisella, Chlamydia, Listeria, Brucella, Helicobacter, Neisseria, and other genera.

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“…Cathepsin C (CTC) is an aminopeptidase that plays key roles in inflammation, IL1β production, TNF-α production, and macrophage reprogramming (56)(57)(58). We therefore used a previously published ratiometric DNA-based lysosomal CTC reporter system to probe CTC activity in vesicular and tubular lysosomes in RAW 264.7 cells and BMDM ( Fig To test whether the differences in lysosomal activity between tubular and vesicular states arose potentially due to selective partitioning of hydrolases between both types of lysosomes(7), we probed the relative abundance of Cathepsin B (CTB) by immunofluorescence.…”

Section: Single Lysosome Protease Activity Maps Reveal That Tubular Lmentioning

confidence: 99%

Tubular lysosomes harbor active ion gradients and poise macrophages for phagocytosis

Suresh

Saminathan

Chakraborty

et al. 2020

Preprint

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Lysosomes adopt dynamic, tubular states that regulate antigen presentation, phagosome resolution and autophagy. To date, tubular lysosomes have been studied either by inducing autophagy or by activating immune cells, both of which lead to cell states where lysosomal gene expression differs from the resting state. Therefore, it has been challenging to pinpoint the specific biochemical properties lysosomes acquire upon tubulation that could drive their functionality. We describe a DNA-based assembly that tubulates lysosomes in macrophages without activating them. Lumenal proteolytic activity maps at single lysosome resolution revealed that tubular lysosomes were less degradative. Further, they showed striking proximal to distal lumenal pH and Ca2+ gradients. Such gradients had been predicted, but never previously observed. We now identify a role for tubular lysosomes whereby they poise resting macrophages for phagocytosis. The ability to tubulate lysosomes without having to starve or activate immune cells may help reveal new roles for tubular lysosomes.

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Up-regulated cathepsin C induces macrophage M1 polarization through FAK-triggered p38 MAPK/NF-κB pathway

Cited by 46 publications

References 37 publications

Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages

Cathepsin Inhibition Modulates Metabolism and Polarization of Tumor-Associated Macrophages

Cathepsins in Bacteria-Macrophage Interaction: Defenders or Victims of Circumstance?

Tubular lysosomes harbor active ion gradients and poise macrophages for phagocytosis

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