Spinal toll-like receptor signaling and nociceptive processing: regulatory balance between TIRAP and TRIF cascades mediated by TNF and IFNß.
Pain
; 154(5): 733-742, 2013 May.
Article
em En
| MEDLINE
| ID: mdl-23489833
ABSTRACT
Toll-like receptors (TLRs) play a pivotal role in inflammatory processes, and individual TLRs have been investigated in nociception. We examined overlapping and diverging roles of spinal TLRs and their associated adaptor proteins in nociceptive processing. Intrathecal (IT) TLR2, TLR3, or TLR4 ligands (-L) evoked persistent (7-day) tactile allodynia (TA) that was abolished in respective TLR-deficient mice. Using Tnf(-/-) mice, we found that IT TLR2 and TLR4 TA was tumor necrosis factor (TNF) dependent, whereas TLR3 was TNF-independent. In Toll-interleukin 1 receptor (TIR) domain-containing adaptor protein (TIRAP; Tirap(-/-)) mice (downstream to TLR2 and TLR4), allodynia after IT TLR2-L and TLR4-L was abolished. Unexpectedly, in TIR-domain-containing adapter-inducing interferon-ß (Trif(lps2)) mice (downstream of TLR3 and TLR4), TLR3-L allodynia was abrogated, but intrathecal TLR4-L produced a persistent increase (>21days) in TA. Consistent with a role for interferon (IFN) ß (downstream to TIR-domain-containing adapter-inducing IFNß [TRIF]) in regulating recovery after IT TLR4-L, prolonged allodynia was noted in Ifnar1(-/-) mice. Further, IT IFNß given to Trif(lps2) mice reduced TLR4 allodynia. Hence, spinal TIR domain-containing adaptor protein (TIRAP) and TRIF cascades differentially lead to robust TA by TNF-dependent and independent pathways, whereas activation of TRIF modulated processing through type I IFN receptors. Based on these results, we believe that processes leading to the activation of these spinal TLRs initiate TNF-dependent and -independent cascades, which contribute to the associated persistent pain state. In addition, TRIF pathways are able to modulate the TNF-dependent pain state through IFNß.
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Base de dados:
MEDLINE
Assunto principal:
Medula Espinal
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Glicoproteínas de Membrana
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Fator de Necrose Tumoral alfa
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Interferon beta
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Receptores de Interleucina-1
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Proteínas Adaptadoras de Transporte Vesicular
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Receptores Toll-Like
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Nociceptividade
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article