Pro Inflammatory Chemokines

Chemokines, a superfamily of chemotactic proteins induced by contact with pathogens, regulate the recruitment of various classes of phago-cytic cells, T cells and eosinophils into sites of infection. Keratinocyte-derived chemokines regulate the migration of leukocytes and neu-trophils from peripheral blood vessels into inflamed skin, in a sequence of tightly controlled events involving the activation of vessel endo-thelium, transendothelial migration and che-motaxis [31, 32].

Skin-pathogenic microorganisms such as S. aureus, B. burgdorferi or C. albicans together with several PAMPs (e.g., LPS or PGN) induce the abundant expression of IL-8 [a chemokine now referred to as CXC chemokine ligand 8 (CXCL8)] in a TLR-NF-kB-pathway-dependent manner [15, 47, 49, 59, 75]. Pathogen-induced secretion of keratinocyte-derived IL-8 initiates neutrophil chemoattraction and transendothe-lial migration. In addition, IL-8 is selectively involved in the transendothelial migration of CLA+ T cells, emphasizing the role of IL-8 in the homing of specific T cells to inflamed skin (Fig. 13.2). In addition to IL-8, pathogens and microbial products, such as heat-killed S. aureus and staphylococcal PGN, stimulate the expression of other chemokines in keratinocytes, such as RANTES/CCL5 (regulated on activation, normal T expressed and secreted, RANTES) or MCP-1/CCL2 (monocyte chemoattractant pro-tein-1) [47]. RANTES-expressing keratinocytes were detected in the lesional skin of patients with atopic dermatitis and psoriasis, implying a role for RANTES in skin inflammation, possibly through the recruitment of distinct leukocyte subsets [19, 24, 63]. MCP-1/CCL2 displays chemotactic activity to blood monocytes, memory T helper cells, and eosinophils but not to neutrophils [23, 24].

Chemokines also exert in vitro antimicrobial properties against a wide variety of microorganisms [30, 78]. Under physiological conditions 20 out of 45 known human chemokines function as potent antimicrobial factors, providing evidence for the close functional and evolutionary relationships between chemokines and antimicrobial peptides [30, 78, 79]. After challenge with microbial constituents or inflammatory signals, many of these "antimicrobial chemokines" are expressed by epidermal keratinocytes (e.g., CCL18, CCL19, CCL20, CCL25, CXCL1, CXCL10), suggesting that keratinocyte-derived chemokines are involved not only in the recruitment of professional immune cells to the sites of infection but in the direct killing of pathogens as well. Still further functional studies are needed to elucidate the exact role chemokines play in the elimination of skin-infecting pathogens.

Pma Activate Cells

Fig. 13.2. Possible function/s of keratinocytes in hi-dradenitis suppurativa (HS). Follicular hyperkeratosis is the initial event of HS, leading to the spilling of keratin and bacteria into the surrounding dermis with resultant secondary infection. Attaching bacteria activate the production of antimicrobial peptides (e.g., hBD-2) and/or pro-inflammatory cytokines/chemokines (IL-1a, IL-1|3, IL-8, IL-6, and TNF-a) in keratinocytes through the activation of TLR/IL-1R-NF-kB signaling. Keratinocyte-derived antimicrobial peptides either kill the pathogens or regulate the recruitment of memory T cells and im-

mature dendritic cells through interaction with CCR6. Additionally, antimicrobial peptides activate immature DCs through TLR4, which leads to the initialization of acquired immune responses. Keratinocyte-derived IL-8 and pro-inflammatory cytokines activate endothe-lial cells allowing the transepithelial migration of neu-trophils. Extravasated neutrophils follow a chemotactic gradient formed by IL-8 toward the site of infection. (DC Dendritic cell, hBD-2 human ß-defensin 2, IL interleu-kin, NF-kB nuclear factor kappa B, TLR Toll-like receptor, TNF tumor necrosis factor)

Fig. 13.2. Possible function/s of keratinocytes in hi-dradenitis suppurativa (HS). Follicular hyperkeratosis is the initial event of HS, leading to the spilling of keratin and bacteria into the surrounding dermis with resultant secondary infection. Attaching bacteria activate the production of antimicrobial peptides (e.g., hBD-2) and/or pro-inflammatory cytokines/chemokines (IL-1a, IL-1|3, IL-8, IL-6, and TNF-a) in keratinocytes through the activation of TLR/IL-1R-NF-kB signaling. Keratinocyte-derived antimicrobial peptides either kill the pathogens or regulate the recruitment of memory T cells and im-

mature dendritic cells through interaction with CCR6. Additionally, antimicrobial peptides activate immature DCs through TLR4, which leads to the initialization of acquired immune responses. Keratinocyte-derived IL-8 and pro-inflammatory cytokines activate endothe-lial cells allowing the transepithelial migration of neu-trophils. Extravasated neutrophils follow a chemotactic gradient formed by IL-8 toward the site of infection. (DC Dendritic cell, hBD-2 human ß-defensin 2, IL interleu-kin, NF-kB nuclear factor kappa B, TLR Toll-like receptor, TNF tumor necrosis factor)

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