Involvement of protein A and IL-16 in the hyperalgesia and allodynia evoked by Staphylococcus aureus in mice.

Staphylococcus aureus is a Gram-positive bacteria that induces painful infections. Since S. aureus releases a protein called staphylococcal protein A (SpA) that can stimulate the release of interleukin IL-16 and the involvement of this interleukin in inflammatory pain has been recently demonstrated in mice, we explored whether SpA and IL-16 participate in S. aureus-evoked hypernociception. The intraplantar (i.pl.) administration of SpA (0.3-3 μg) produced thermal hyperalgesia and mechanical allodynia prevented by an anti-IL-16 antibody (0.3-1 μg/kg). Moreover, the i.pl. inoculation of S. aureus (103-106 CFU, 6 h before) induced hyperalgesia and allodynia together with an increase of local concentrations of IL-16 and the up-regulation of caspase-3 mRNA. Immunofluorescence assays indicated that neutrophils are the main cells expressing IL-16 after S. aureus i.pl. injection. Supporting the involvement of IL-16, antibodies against IL-16 (1-30 μg/kg) or CD4 receptors (1-30 μg/kg) inhibited hyperalgesia and allodynia evoked by this microorganism. In contrast, the anti-IL-16 antibody did not alter hypernociception produced by Streptococcus pyogenes, another Gram-positive bacteria unrelated to SpA. Since septic arthritis is one of the main clinical entities related to S. aureus-induced pain, we inoculated S. aureus (2 × 105 CFU, 5 days before) into the knee. Hyperalgesia, allodynia and local IL-16 up-regulation were observed, being the presence of IL-16 mainly related to macrophage-like synovial cells and fibroblasts. Accordingly, the anti-IL-16 antibody also completely prevented hypernociceptive reactions in these mice. Overall, the present results support the possible relevance of IL-16 as an innovative target for the control of pain during S. aureus infections.