Six-transmembrane epithelial antigens of the prostate comprise a novel
inflammatory nexus in patients with pustular skin disorders
#MMPMID27884600
Liang Y
; Xing X
; Beamer MA
; Swindell WR
; Sarkar MK
; Roberts LW
; Voorhees JJ
; Kahlenberg JM
; Harms PW
; Johnston A
; Gudjonsson JE
J Allergy Clin Immunol
2017[Apr]; 139
(4
): 1217-1227
PMID27884600
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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
3 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
biopsy specimens obtained from patients with GPP, PPP, or AGEP and healthy
control subjects. Functional enrichment, gene network, and k-means clustering
analyses were used to identify molecular pathways dysregulated in patients with
these disorders. Immunohistochemistry and immunofluorescence were used to
determine protein localization. Quantitative RT-PCR and ELISA were used to
determine transcript and secreted cytokine levels. Small interfering RNA was used
to decrease transcript levels. RESULTS: Molecules and pathways related to
neutrophil chemotaxis emerged as common alterations in patients with GPP, PPP,
and AGEP, which is consistent with the pustular phenotypes. Expression of two
6-transmembrane epithelial antigens of the prostate (STEAP) proteins, STEAP1 and
STEAP4, was increased in patients' skin and colocalized with IL-36? around
neutrophilic pustules. STEAP1/4 expression clustered with and positively
correlated with that of IL-1, the IL-36 family proteins, and CXCL1/8. STEAP4
expression was activated by cytokines and suppressed by inhibition of
mitogen-activated protein kinase kinase 1/2, whereas STEAP1 expression appeared
less prone to such dynamic regulation. Importantly, STEAP1/4 knockdown resulted
in impaired induction of a broad spectrum of proinflammatory cytokines, including
IL-1, IL-36, and the neutrophil chemotaxins CXCL1 and CXCL8. STEAP1/4 knockdown
also reduced the ability of keratinocytes to induce neutrophil chemotaxis.
CONCLUSION: Transcriptomic changes in 3 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.
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