Cysteine-type cathepsins promote the effector phase of acute cutaneous delayed-type hypersensitivity reactions

Abstract

Cysteine-type cathepsins such as cathepsin B are involved in various steps of inflammatory processes such as antigen processing and angiogenesis. Here, we uncovered the role of cysteine-type cathepsins in the effector phase of T cell-driven cutaneous delayed-type hypersensitivity reactions (DTHR) and the implication of this role on therapeutic cathepsin B-specific inhibition. Methods : Wild-type, cathepsin B-deficient (Ctsb -/- ) and cathepsin Z-deficient (Ctsz -/- ) mice were sensitized with 2,4,6-trinitrochlorobenzene (TNCB) on the abdomen and challenged with TNCB on the right ear to induce acute and chronic cutaneous DTHR. The severity of cutaneous DTHR was assessed by evaluating ear swelling responses and histopathology. We performed fluorescence microscopy on tissue from inflamed ears and lymph nodes of wild-type mice, as well as on biopsies from psoriasis patients, focusing on cathepsin B expression by T cells, B cells, macrophages, dendritic cells and NK cells. Cathepsin activity was determined noninvasively by optical imaging employing protease-activated substrate-like probes. Cathepsin expression and activity were validated ex vivo by covalent active site labeling of proteases and Western blotting. Results : Noninvasive in vivo optical imaging revealed strong cysteine-type cathepsin activity in inflamed ears and draining lymph nodes in acute and chronic cutaneous DTHR. In inflamed ears and draining lymph nodes, cathepsin B was expressed by neutrophils, dendritic cells, macrophages, B, T and natural killer (NK) cells. Similar expression patterns were found in psoriatic plaques of patients. The biochemical methods confirmed active cathepsin B in tissues of mice with cutaneous DTHR. Topically applied cathepsin B inhibitors significantly reduced ear swelling in acute but not chronic DTHR. Compared with wild-type mice, Ctsb -/- mice exhibited an enhanced ear swelling response during acute DTHR despite a lack of cathepsin B expression. Cathepsin Z, a protease closely related to cathepsin B, revealed compensatory expression in inflamed ears of Ctsb -/- mice, while cathepsin B expression was reciprocally elevated in Ctsz -/- mice. Conclusion : Cathepsin B is actively involved in the effector phase of acute cutaneous DTHR. Thus, topically applied cathepsin B inhibitors might effectively limit DTHR such as contact dermatitis or psoriasis. However, the cathepsin B and Z knockout mouse experiments suggested a complementary role for these two cysteine-type proteases.

Dihydroartemisinin ameliorates psoriatic skin inflammation and its relapse by diminishing CD8+ T-cell memory in wild-type and humanized mice

“…Psoriasis is an immune-mediated chronic skin disease, which is prone to relapse and affects approximately 2% of the population worldwide 1 . Although the pathogenesis of psoriasis remains unclear, it has been widely recognized that T cells, especially CD4 + Th17 and IL-17-producing γδ T cells, play an important role in the development and progression of psoriasis 2 , 3 and cutaneous DTH responses 4 . The accumulation of Th17 cells in the dermis can lead to the aberrant differentiation and proliferation of keratinocytes by producing abundant proinflammatory cytokines, such as IL-6, IL-17A and IL-22 5 .…”

Single-cell RNA-Seq reveals the transcriptional landscape and heterogeneity of skin macrophages in Vsir-/- murine psoriasis

“…The multifactorial pathogenesis contributing to the psoriasis phenotype involves genetic, environmental and immunological factors 2 . Psoriasis is generally manifested as chronic inflammation of the skin and is characterized by circumscribed, scaling, and erythaematous plaques 3 , 4 .…”

NLRP3 Inflammasome and Allergic Contact Dermatitis: A Connection to Demystify

“…The authors also showed a redundancy in cathepsin function, with cathepsin Z, a protease closely related to cathepsin B, showing a compensatory expression in inflamed ears of cathepsin B-deficient (Ctsb −/− ) mice. In turn, cathepsin B expression was equally elevated in cathepsin Z-deficient (Ctsz −/− ) mice [ 89 ]. Interestingly, the functional redundancy of cathepsins was also reported by Orlowski and colleagues, which demonstrated that although being involved in IL-1β secretion, cathepsins also regulate pro-IL-1β synthesis [ 90 ].…”