Imidazoquinoline Toll-like receptor 8 agonists activate human newborn monocytes and dendritic cells through adenosine-refractory and caspase-1-dependent pathways

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• 作者：Victoria J. Philbin ; David J. Dowling ; Leighanne C. Gallington ; Guadalupe Cort¨¦s ; Zhen Tan ; Eug¨¦nie E. Suter ; Kevin W. Chi ; Ariel Shuckett ; Liat Stoler-Barak ; Mark Tomai ; Richard L. Miller ; Keith Mansfield ; Ofer Levy
• 关键词：Toll-like receptor 8 ; innate immunity ; neonate ; newborn ; alum ; adjuvant ; adenosine ; IL-1¦Â ; caspase-1 ; inflammasome
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2012
• 出版时间：July, 2012
• 年：2012
• 卷：130
• 期：1
• 页码：195-204.e9
• 全文大小：2147 K

文摘

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Background

Newborns have frequent infections and manifest impaired vaccine responses, motivating a search for neonatal vaccine adjuvants. Alum is a neonatal adjuvant but might confer a T_H2 bias. Toll-like receptor (TLR) agonists are candidate adjuvants, but human neonatal cord blood monocytes demonstrate impaired T_H1-polarizing responses to many TLR agonists caused by plasma adenosine acting through cyclic AMP. TLR8 agonists, including imidazoquinolines (IMQs), such as the small synthetic 3M-002, induce adult-level TNF from neonatal monocytes, but the scope and mechanisms of IMQ-induced activation of neonatal monocytes and monocyte-derived dendritic cells (MoDCs) have not been reported.

Objective

We sought to characterize IMQ-induced activation of neonatal monocytes and MoDCs.

Methods

Neonatal cord and adult peripheral blood monocytes and MoDCs were cultured in autologous plasma; levels of alum- and TLR agonist-induced cytokines and costimulatory molecules were measured. TLR8 and inflammasome function were assayed by using small interfering RNA and Western blotting/caspase-1 inhibitory peptide, respectively. The ontogeny of TLR8 agonist-induced cytokine responses was defined in rhesus macaque whole blood ex?vivo.

Results

IMQs were more potent and effective than alum at inducing TNF and IL-1¦Â from monocytes. 3M-002 induced robust TLR pathway transcriptome activation and T_H1-polarizing cytokine production in neonatal and adult monocytes and MoDCs, signaling through TLR8 in an adenosine/cyclic AMP-refractory manner. Newborn MoDCs displayed impaired LPS/ATP-induced caspase-1-mediated IL-1¦Â production but robust 3M-002-induced caspase-1-mediated inflammasome activation independent of exogenous ATP. TLR8 IMQs induced robust TNF and IL-1¦Â in whole blood of rhesus macaques at birth and infancy.

Conclusions

IMQ TLR8 agonists engage adenosine-refractory TLR8 and inflammasome pathways to induce robust monocyte and MoDC activation and represent promising neonatal adjuvants.