Lipopolysaccharide Induces Inflammatory Hyperalgesia Triggering a TLR4/MyD88-Dependent Cytokine Cascade in the Mice Paw

Author(s)

Calil, Igor L. ^[1] ; Zarpelon, Ana C. ^[2] ; Guerrero, Ana T. G. ^[3] ; Alves-Filho, Jose C. ^[1] ; Ferreira, Sergio H. ^[1] ; Cunha, Fernando Q. ^[1] ; Cunha, Thiago M. ^[1] ; Verri, Jr., Waldiceu A. ^[2]

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Sao Paulo - Brazil

^[2] Univ Estadual Londrina, Ctr Ciencias Biol, Dept Patol, Londrina, Parana - Brazil

^[3] FIOCRUZ Mato Grosso Sul, Campo Grande, MS - Brazil

• Document type: Journal article
• Source: PLoS One; v. 9, n. 3 MAR 3 2014.
• Web of Science Citations: 43

Abstract

Inflammatory pain can be triggered by different stimuli, such as trauma, radiation, antigen and infection. In a model of inflammatory pain caused by infection, injection in the mice paw of lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) agonist, produces mechanical hyperalgesia. We identify here the TLR4 linked signaling pathways that elicit this response. Firstly, LPS paw injection in wild type (WT) mice produced mechanical hyperalgesia that was not altered in TRIF-/- mice. On the other hand, this response was absent in TLR4 mutant and MyD88 null mice and reduced in TNFR1 null mice. Either an IL-1 receptor antagonist, anti-KC/CXCL1 antibody, indomethacin or guanethidine injection also lessened this response. Moreover, LPS-induced time dependent increases in TNF-alpha, KC/CXCL1 and IL-1 beta expression in the mice paw, which were absent in TLR4 mutant and MyD88 null mice. Furthermore, in TNFR1 deficient mice, the LPS-induced rises in KC/CXCL1 and IL-1 beta release were less than in their wild type counterpart. LPS also induced increase of myeloperoxidase activity in the paw skin, which was inhibited in TLR4 mutant and MyD88 null mice, and not altered in TRIF-/- mice. These results suggest that LPS-induced inflammatory pain in mice is solely dependent on the TLR4/MyD88 rather than the TLR4/TRIF signaling pathway. This pathway triggers pronociceptive cytokine TNF-alpha release that in turn mediates rises in KC/CXCL1 and IL-1 beta expression. Finally, these cytokines might be involved in stimulating production of directly-acting hyperalgesic mediators such as prostaglandins and sympathomimetic amine. (AU)

• FAPESP's process: 11/19670-0 - Mechanisms involved in the pathophysiology of rheumatoid arthritis, pain and sepsis
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Projects - Thematic Grants