Neutrophil-Activating Proteins in Psoriasis

Schröder, Jens‐M.; Gregory, H.; Young, J.; Christophers, Enno

doi:10.1111/1523-1747.ep12556058

Cited by 138 publications

(81 citation statements)

References 37 publications

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“…As IL-8 secreted by a variety of inflammatory cells including monocytes has been implicated in a number of inflammatory/infectious diseases, such as rheumatoid arthritis [33], inflammatory bowel disease [34], psoriasis [35,36], palmoplantar pustulosis [37,38], asthma and chronic obstructive pulmonary disease [39], targeting P2Y 2 and/or P2Y 6 receptors may reveal as novel therapeutic approaches to fight these diseases. These data are also in agreement with a new concept proposing that extracellular nucleotides serve as endogenous danger-signaling molecules called alarmins that are (10 ng/mL) for 5 h in the presence or absence of semi-purified apyrase (2 U/mL) and/or P2 receptor antagonists (100 mM RB2, suramin, PPADS, or 10 mM MRS2578, respectively).…”

Section: Discussionmentioning

confidence: 99%

Concomitant activation of P2Y₂ and P2Y₆ receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

et al. 2009

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Extracellular nucleotides regulate a variety of cellular responses involved in inflammation via the activation of P2 receptors. Here, we show that nucleotides regulate TLR2-induced neutrophil migration both in vivo and in vitro. The nucleotide scavenger apyrase inhibited neutrophil recruitment in murine air pouches injected with the TLR2 agonist Pam 3 CSK 4 . In agreement, the supernatants of either human primary monocytes or monocytic cells (THP-1 and U937) treated with Pam 3 CSK 4 recruited significantly fewer neutrophils when the former cells were treated in the presence of apyrase. As demonstrated with inhibitory Ab, these supernatants induced neutrophil migration due to IL-8 secretion. In addition, IL-8 secretion was markedly diminished by the non-selective P2 receptor antagonists reactive blue 2 and suramin, and by a selective P2Y 6 antagonist, MRS2578. Selective antagonists of P2Y 1 (MRS2500) and P2Y 11 (NF157) did not affect IL-8 release. The knockdown of either P2Y 2 or P2Y 6 with specific shRNA diminished IL-8 secretion from Pam 3 CSK 4 -treated THP-1 cells. Altogether, these results show that extracellular nucleotides, via P2Y 2 and P2Y 6 receptors, regulate neutrophil migration by controlling TLR2-induced IL-8 release from human monocytes. In line with our previous work on TLR4, this study further supports the importance of nucleotides in bacterial-induced neutrophil migration.Key words: Cell trafficking . Human monocytes . Inflammation . Neutrophils . Pam 3 CSK 4 IntroductionMonocytes play an important role in immune defences against invading bacteria and viruses via TLR activation [1]. TLR recognize highly conserved structural motifs expressed by microbes called PAMP. Monocytes express various TLR including TLR4 (that is activated by LPS, a cell wall component of Gramnegative bacteria), TLR2 (activated by peptidoglycan and lipopeptide, components of Gram-positive bacteria), TLR5 (activated by the bacterial flagellin) and TLR7/8 (activated by single-stranded viral RNA) [2][3][4][5]. In response to TLR activation by PAMP, monocytes release various cytokines and chemokines that orchestrate the innate immune responses [6][7][8]. For example, these cells secrete large amounts of the chemokine IL-8 that plays a major role in neutrophil recruitment at sites of infection [9].In addition to TLR, monocytes abundantly express P2 receptors that are activated by extracellular nucleotides. P2 receptors are divided into two subfamilies: the G-protein-coupled receptors (P2Y 1,2,4,6,[11][12][13][14] ) and the ligand-gated ion channels (P2X 1-7 ). The P2Y subtypes differ in their selectivity toward adenine (ATP, ADP) and uracil nucleotides (UTP, UDP) while all P2X receptors are activated by ATP [10,11]. Human primary monocytes and monocytic cell lines (THP-1 and U937) express the mRNA of various P2 receptors of which P2X 1,7 and P2Y 2,6,11 are common to all these cells [12,13]. There is growing evidence indicating that Results Extracellular nucleotides are involved in Pam 3 CSK 4 -induced neutrophil migration in vi...

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Section: Discussionmentioning

confidence: 99%

Concomitant activation of P2Y₂ and P2Y₆ receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

et al. 2009

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“…*p Ͻ 0.05 versus medium only. 1990; Nickoloff et al, 1991;Anttila et al, 1992;Schrö -der et al, 1992;Schulz et al, 1993;Gillitzer et al, 1991;Gillitzer et al, 1996;Schmidt, 1996), though not with pyoderma gangrenosum (Marie et al, 1999). We observed overexpression of IL-8 in areas of inflammation, with expression primarily in neutrophils in clinical specimens with pyoderma gangrenosum and in fibroblasts in experimental specimens that showed histologic changes reminiscent of pyoderma gangrenosum.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, high levels of IL-8 have been detected during acute inflammatory reactions (Garner et al, 1994;Ono et al, 1995;Strickland et al, 1997;Zweiman et al, 1997); in chronic skin diseases such as psoriasis vulgaris (Gearing et al, 1990;Nickoloff et al, 1991;Anttila et al, 1992;Schrö der et al, 1992;Schulz et al, 1993;Gillitzer et al, 1991;Gillitzer et al, 1996), palmoplantar pustulosis (Anttila et al, 1992), and bullous pemphigoid (Schmidt, 1996); and in nonmelanoma and melanoma skin tumors (Hansen et al, 1991;Ciotti et al, 1995;Bornscheuer et al, 1996). However, the role of IL-8 in the pathogenesis of skin diseases has been difficult to elucidate because of the abundance of other cytokines that can induce IL-8 expression.…”

mentioning

confidence: 99%

Interleukin-8 Overexpression Is Present in Pyoderma Gangrenosum Ulcers and Leads to Ulcer Formation in Human Skin Xenografts

Oka

Berking

Nesbit

et al. 2000

Laboratory Investigation

113

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SUMMARY: ) is a potent chemotactic polypeptide for neutrophils. However, the role of this cytokine during inflammation remains unclear. Skin specimens from patients with pyoderma gangrenosum demonstrated IL-8 overexpression in skin ulcers, which suggests a role for IL-8 in the development of the disease. We therefore constructed a recombinant adenovirus expressing the complementary deoxyribonucleic acid encoding human IL-8 (IL-8/Ad5) that induces a 2000-fold increase in IL-8 expression of infected human fibroblasts in vitro. Human skin engrafted to severe combined immunodeficiency mice and then injected with the recombinant virus demonstrated erythema, an intense perivascular infiltration of neutrophils, and extravasation of erythrocytes after 8 hours. By 12 hours after injection, neutrophils had accumulated beneath the epidermis, which then necrotized, and one or more ulcers that remained for approximately 2 weeks were observed. Clinically and histologically, the ulcers resembled pyoderma gangrenosum. These clinical and experimental findings suggest an etiologic role of IL-8 in the pathogenesis of pyoderma gangrenosum. (Lab Invest 2000, 80:595-604).

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“…NK cell migration in response to keratinocyte supernatants was significantly reduced by anti-CCR5 and anti-CXCR3 treatment but not by pre-incubation of NK cells with anti-CCR6. Despite elevated CXCL8 levels in psoriatic skin [52] and expression of the chemokine receptor CXCR1 on infiltrating T lymphocytes and NK cells, both failed to respond in vitro to the chemokines, in line with the hypothesis that CXCL8 has chemokinetic but not chemoattractant properties on NK lymphocytes [53,54]. In comparison to NK cells, psoriatic T lymphocytes displayed a wider range of chemokine receptors and responded to a multitude of chemotactic factors, including CCL17, CCL20, CX3CL1 and CCL1 as well as CXCL10 and CCL5.…”

Section: Cd16mentioning

confidence: 99%

CD56^brightCD16^– NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation

et al. 2005

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Psoriasis is an immune-mediated skin disease characterized by lymphocytic infiltration and altered keratinocyte differentiation. Using immunohistochemical techniques we found that the cellular infiltrate in acute psoriatic plaques includes 5-8% CD3 -CD56 + natural killer (NK) cells, mostly localized in the mid and papillary dermis. NK lymphocytes isolated from punch biopsy specimens of psoriatic plaques showed a CD56 bright CD16 -CD158b -phenotype, failed to express the skin homing cutaneous lymphocyte-associated antigen and released abundant IFN-c upon stimulation. Supernatants from psoriatic NK cells induced MHC class II and ICAM-1 expression and release of CXCL10 and CCL5 by cultured psoriatic keratinocytes. Skin NK cells expressed high levels of the chemokines receptors CXCR3 and CCR5, intermediate amounts of CXCR1, CCR6 and CCR8, and low levels of CCR1, CCR2, CCR4, CCR7 and CX3CR1. In addition, they promptly migrated in vitro toward CXCL10, CCL5, supernatants of IFN-c-activated psoriatic keratinocytes and, to a lower extent, CCL20 and CCL4. In contrast, they failed to migrate toward CXCL8, CCL1, CCL2, CCL3, CCL17, CCL19 and CX3CL1. Taken together, our results implicate NK lymphocytes as newly identified protagonists in the pathogenesis of psoriasis. Their distinctive homing properties should be taken into account in the design of specific therapy aimed at blocking pathogenic cell accumulation in the skin.

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Neutrophil-Activating Proteins in Psoriasis

Cited by 138 publications

References 37 publications

Concomitant activation of P2Y₂ and P2Y₆ receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

Concomitant activation of P2Y₂ and P2Y₆ receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

Interleukin-8 Overexpression Is Present in Pyoderma Gangrenosum Ulcers and Leads to Ulcer Formation in Human Skin Xenografts

CD56^brightCD16^– NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation

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Neutrophil-Activating Proteins in Psoriasis

Cited by 138 publications

References 37 publications

Concomitant activation of P2Y2 and P2Y6 receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

Concomitant activation of P2Y2 and P2Y6 receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

Interleukin-8 Overexpression Is Present in Pyoderma Gangrenosum Ulcers and Leads to Ulcer Formation in Human Skin Xenografts

CD56brightCD16– NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation

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Concomitant activation of P2Y₂ and P2Y₆ receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

Concomitant activation of P2Y₂ and P2Y₆ receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

CD56^brightCD16^– NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation