UV-Induced Neutrophil Infiltration and Increased MMP Secretion in Photo Skin Aging

The primary mechanism of photo skin aging is mediated by UV induced reactive oxygen species (ROS). ROS damages biomacromolecules and function as intracellular signal to activate transcription factors AP-1 and NF-kB . AP-1 And NF-kB are known to regulate a wide varieties of genes that are essential components of chronological and photo skin aging processes. One group of effector protein in skin aging of AP-1 signal transduction pathway is the induction of matrix metalloproteinases (MMP) – the extracellular matrix enzyme synthesized mainly by dermal fibroblast whose function is to degrade extra cellular matrix protein – collagen and elastin – the structural protein fiber network in the dermis connective tissue that account for skin’s strength and elasticity. Both chronologic and photo skin aging is associated with increased MMP and increased degradation of matrix collagen and elastic fiber.

UV irradiation induces MMP-1. MMP-3, MMP-9 significantly, each belong to one of the three main functional subgroups of MMP – the collagenases, stromelysins, and gelatinases. MMP-1 (collagenase 1) is synthesized by keratinocytes and fibroblasts and degrades the Collagens I, II, III, VII and X. Collagen I and III is the major collagen type forming dermis fiber network of the skin, collagen VII is the component in skin’s base membrane at the dermal-epidermal junction (DEJ). Stromelysin (MMP-3) degrades collagen types II, III, IV, IX, and X, proteoglycans, fibronectin, laminin, and elastin. Collagen IV and laminin is the main components in the basal lamina of the base membrane. Gelatinase (MMP-9) degrades type IV and V collagens. Together, these three MMPs can fully degrade skin collagen. Initially, MMP-1 cleaves the triple-helical collagen molecule into three-quarter and one-quarter length fragments which are further degraded by MMP-3 and MMP-9.

UV irradication induces infiltration of neutrophils in the skin and is involved in the UV-induced inflammaging mechanism of skin aging. They are packed with proteolytic enzymes, including MMP and neutrophil elastase. Furthermore, activated neutrophils generate and release ROS. Infiltrating neutrophils can thus damage collagen fibers and elastic fibers. Research data suggests that neutrophils, rather than keratinocytes and fibroblasts, may be the major sources of proteolytic enzymes (particular MMPs and neutrophil elastase) in photo skin aging in vivo. Similar to other cells including fibroblasts, these proteolytic enzymes are normally stored in vesicles in an inactive form. The probable mechanism by which neutrophil-derived proteolytic enzymes are activated (and/or prevented from being inactivated by antiproteinases) is through proteolytic or oxidative mechanisms. ProMMPs can be activated by proteolytic mechanism (by active MMPs or other serine proteases) while antiproteinases can be inactivated by certain oxygen metabolites.

MMP-8 or neutrophil collagenase is a collagenase mainly synthesized by neutrophils. MMP-8 cleaves type I collagen faster than type III collagen, whereas MMP-1 has more specificity to type III collagen relative to type I collagen. Both MMP-1 and MMP-8 are synthesized as latent proenzymes that require proteolytic processing to become catalytically active. Whereas MMP-1 is synthesized and released from cells into the extracellular matrix, however, MMP-8 is synthesized and stored in specific granules in neutrophil. MMP-8 activity is therefore regulated by factors such as surface-bound ligands (IgG or complement components) that release it through degranulation. Once released and activated through proteolytic or oxidative mechanisms, MMP-8 has a major role in the connective tissue turnover. Research has shown that UV irradiation increases MMP-8 activity in vivo in the skin. Proenzyme form of MMP-8 increased significantly within 8 h post UV irradiation. Increased MMP-8 protein was associated with infiltration into the skin of neutrophils.

 

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