Substance P augments chemokine production by Staphylococcus aureus infected murine osteoclasts

Staphylococcal osteomyelitis is a serious infection of the bone and joints characterized by progressive inflammatory tissue damage and leukocyte recruitment leading to net bone loss. Resident bone cells are capable of recognizing Staphylococcus aureus and initiating an inflammatory immune response that recruits leukocytes and alters bone homeostasis. Importantly, bone tissue is richly innervated with substance P containing nerve fibers and we have previously shown that this neuropeptide can augment the inflammatory responses of both osteoblasts and osteoclasts to S. aureus infection via neurokinin-1 receptors (NK-1R). Here, we have extended these studies by demonstrating that pharmacological inhibition of NK-1R ameliorates disease severity in a mouse model of staphylococcal osteomyelitis. This effect was associated with the abolition of infection-induced increases in neutrophil-attracting chemokine production, and reduced local levels of osteoclast and neutrophil activity. We then assessed the effect of S. aureus infection on bone-marrow derived osteoclast gene expression in the absence or presence of substance P. We determined that infection upregulates osteoclast expression of mRNAs encoding inflammatory mediators that include the neutrophil-attracting chemokines identified in vivo. Importantly, we found that, while substance P has no effect on chemokine mRNA expression in infected cells, this neuropeptide significantly increases the release of these chemokines by S. aureus challenged osteoclasts but not osteoblasts. Together, these data further support the ability of substance P to exacerbate inflammatory damage in staphylococcal osteomyelitis and indicate that this effect may be due, in part, to an augmentation of the leukocyte-recruiting immune functions of osteoclasts.