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Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 J+Allergy+Clin+Immunol 2017 ; 139 (4): 1217-27 Nephropedia Template TP
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STEAPs comprise a novel inflammatory nexus in pustular skin disorders #MMPMID27884600
J Allergy Clin Immunol 2017[Apr]; 139 (4): 1217-27 PMID27884600show ga
Background: Pustular skin disorders are a category of difficult-to-treat and potentially life threatening conditions that involve the appearance of neutrophil rich pustules. The molecular basis of most pustular skin conditions has remained unknown. Objective: We sought to investigate the molecular basis of three pustular skin disorders, generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), and acute generalized exanthematous pustulosis (AGEP). Methods: Microarray analyses were performed to profile genome-wide gene expression of skin biopsies obtained from GPP, PPP, AGEP patients and normal controls. Functional enrichment, gene network and k-means clustering analyses were used to identify molecular pathways dysregulated in the disorders. Immunohistochemistry and immunofluorescence were used to determine protein localization. qRT-PCR and ELISA were used to determine transcript and secreted cytokine levels. siRNA was employed to decrease transcript levels. Results: Molecules and pathways related to neutrophil chemotaxis emerged as common alterations in GPP, PPP, and AGEP, consistent with the pustular phenotypes. Expression of two STEAP proteins, STEAP1 and 4, were elevated in patient skin, and co-localized with IL-36? around neutrophilic pustules. STEAP1/4 expression clustered with and positively correlated with that of the IL-1, IL-36 family proteins, and CXCL1/8. STEAP4 expression was activated by cytokines and suppressed by inhibition of MEK1/2, whereas STEAP1 expression appeared less prone to such dynamic regulation. Importantly, STEAP1/4 knockdown resulted in impaired induction of a broad spectrum of pro-inflammatory cytokines including IL-1, IL-36, and neutrophil chemotaxins; CXCL1 and CXCL8. STEAP1/4 knockdown also reduced the ability of keratinocytes to induce neutrophil chemotaxis. Conclusion: Transcriptomic changes in three pustular skin disorders GPP, PPP, and AGEP converged on neutrophil chemotaxis and diapedesis and cytokines known to drive neutrophil rich inflammatory processes including IL-1 and members of the IL-36 family. STEAP1 and STEAP4 positively regulate the induction of proinflammatory, neutrophil-activating cytokines.