Potential Role of Cytochrome c and Tryptase in Psoriasis and Psoriatic Arthritis Pathogenesis: Focus on Resistance to Apoptosis and Oxidative Stress

Abstract

Psoriasis (PsO) is an autoimmune disease characterized by keratinocyte proliferation, chronic inflammation and mast cell activation. Up to 42% of patients with PsO may present psoriatic arthritis (PsA). PsO and PsA share common pathophysiological mechanisms: keratinocytes and fibroblast-like synoviocytes are resistant to apoptosis: this is one of the mechanism facilitating their hyperplasic growth, and at joint level, the destruction of articular cartilage, and bone erosion and/or proliferation. Several clinical studies regarding diseases characterized by impairment of cell death, either due to apoptosis or necrosis, reported cytochrome c release from the mitochondria into the extracellular space and finally into the circulation. The presence of elevated cytochrome c levels in serum has been demonstrated in diseases as inflammatory arthritis, myocardial infarction and stroke, and liver diseases. Cytochrome c is a signaling molecule essential for apoptotic cell death released from mitochondria to the cytosol allowing the interaction with protease, as the apoptosis protease activation factor, which lead to the activation of factor-1 and procaspase 9. It has been demonstrated that this efflux from the mitochondria is crucial to start the intracellular signaling responsible for apoptosis, then to the activation of the inflammatory process. Another inflammatory marker, the tryptase, a trypsin-like serine protease produced by mast cells, is released during inflammation, leading to the activation of several immune cells through proteinase-activated receptor-2. In this review, we aimed at discussing the role played by cytochrome c and tryptase in PsO and PsA pathogenesis. To this purpose, we searched pathogenetic mechanisms in PUBMED database and review on oxidative stress, cytochrome c and tryptase and their potential role during inflammation in PsO and PsA. To this regard, the cytochrome c release into the extracellular space and tryptase may have a role in skin and joint inflammation.

Keywords: apoptosis; autoimmunity; cytochrome c and tryptase; oxidative stress; psoriatic arthritis; psoriatic disease.

Figure 1

Three-dimensional structure of Cytochrome c and Tryptase (A) Horse heart cytochrome c structure characterized by X-ray crystallography (6). In the inset, the fifth and sixth ligands (His 18 and Met 80, respectively) to the Fe-Heme are shown. (B) Human β-tryptase tetramer structure as determined by X-ray crystallography (11). (C) Tryptase monomer structure: the catalytic triad residues (Ser 195, His 57, and Asp 102) are highlighted.

Figure 2

Mechanisms involved in Psoriasis arthritis pathogenesis. In a summary view, environmental triggers induce the expression of autoantigens, such as LL37 by keratinocytes, ADAMTSL5 by melanocytes, and lipid antigen by mast cells. This leads to expansion and activation of autoreactive CD8 and CD4 T cells. Although CD4 T cells remain within the dermis producing a large plethora of inflammatory cytokines, activated CD8 T cells migrate into the epidermis. Subsequently, potentially upon recognition of autoantigens in the epidermis CD8 T cells release other inflammatory mediators, which in turn mediate skin cell homing and remain as resident memory T cells in the epidermis. All this inflammatory process is maintained and amplified by oxidative stress sustained by production of NADPH-oxidase (NOX), inducible nitric oxide synthase (iNOS) myeloperoxidase (MPO), malondialdehyde (MDA), nitric oxide (NO), and serum cytochrome c and decreased of antioxidant status such as superoxide dismutase (SOD), catalase (CAT).

Figure 3

Mechanisms involved in Psoriatic arthritis pathogenesis. The figure summarizes the pathogenesis of Psoriatic arthritis (PsA). The enthesitis seems to be the primum movens of the disease, even if the heterogeneity of systemic involvement and clinical manifestations is extremely wide (31). Genetic and environmental factors predispose a healthy individual and contribute to the development of the disease. Mitochondrial dysfunction, angiogenesis and increased production of reactive oxygen species (ROS) seem to be present since the early disease onset. The role of the innate immunity in the tolerance disruption and in the production of a pro-inflammatory milieu is very early and essential in the pathogenesis of both PsA and Psoriasis. Adaptive immunity participates later by perpetuating and further increasing the inflammation. Several soluble mediators, such as pro-inflammatory cytokines and proteases, can be found in the synovial fluid and sera of PsA patients.