Table 1 The status and pathophysiological effects of CTSS in pulmonary and extra-pulmonary diseases

COPD

Elevated in smokers and COPD patients

Active in healthy lung at neutral pH, which could influence disease initiation

CTSS regulates lung inflammation and epithelial apoptosis

CTSS levels corresponds to disease severity, i.e. FEV₁/FVC and DLCO%

PP2A activators reduced CTSS expression and lung function decline in vivo

[57,58,59]

Asthma

CTSS genetic polymorphisms are linked to susceptibility of patients to asthma

CTSS-induced atopic dermatitis in mice PAR2 pathway results in CD4+ T cell differentiation, which is also involved in MHC class II expression

Methylprednisone reduced serum CTSS levels.

CTSS inhibitor decreased inflammation and the number of eosinophils

[60,61,62,63,64,65]

PAH

Elevated CTSS in PAH patients and reduced elastic lamina and subsequent smooth muscle hypertrophy

Linked to atheroma formation and vascular remodeling in humans and rodent disease models.

Osthole modulated CTSS responses and reduced PAH in rats

[66,67,68]

Cystic Fibrosis

Negative correlation with lung function

Causes epithelial activation of the sodium channel, cleavage of surfactants, inactivation of βdefensins, and mucus production

CTSS inhibitor VBY-999 decreased inflammation, lung damage and mucous plugging in the lungs, partially via inhibition of PAR2

[69,70,71,72,73]

Cancer

High levels of CTSS expression in circulating tumor cells of SCLC

CTSS-degraded Decorin

Ctss^−/− mice exhibit impaired micro-vessel growth during wound healing,

In vivo inhibition of CTSS decreased tumor growth in colorectal tumor models but unknown in lung cancer

[18, 74,75,76,77,78]

Sarcoidosis

Elevated CTSS levels in serum and histology samples

CTSS correlates with sarcoid diagnosis

[79]

IPF

High levels of CTSS expression

CTSS expression predicts disease progression

[80, 81]

Extra-pulmonary diseases and outcomes

CTSS signaling

Pathology

Potential therapeutics

References

Muscle function

Ctss^−/− mice have healthier skeletal muscle, reduced myofiber degeneration, fibrosis and improved running performance

Targeting of CTSS may improve muscle function

[82]

Sjögren’s syndrome

Elevated CTSS in patient tears

CTSS degrades tear proteins

CTSS inhibitor reduced symptoms in a mouse model

[83, 84]

Lupus

CTSS influences MHC class II-processing and T and B cell priming

[85]

Autoimmune encephalomyelitis

Double knockout of Ctsb and Ctss modulates MHC-II processing/presentation of myelin oligodendrocyte glycoprotein

Double knockout of Ctsb and Ctss protected mice from experimental autoimmune encephalomyelitis

[86]

Cardiovascular disease

CTSS is elevated in atheromas and in their surrounding tissues

Ctss^−/−ApoE^−/− mice in a model of abdominal aortic aneurysm have reduced disease progression

CTSS inhibitor, RO5444101, decreased osteogenic activity, elastin degradation, plaque size, macrophage accumulation, growth differentiation factor-15, and calcification

[87,88,89]

Diabetes and obesity

CTSS levels reduce after gastric surgery

Ctss deficiency reduces blood glucose

Orally active small-molecule CTSS inhibitors reduced hepatic glucose production

[90, 91]

Pain

Elevated CTSS are observed in chronic colitis

CX3CL1/fractalkine is cleaved by CTSS resulting in the promoting of pain signaling.

CTSS expression promotes itch, via PAR2/4-signaling

[92,93,94]