|Table 1. Substance P Facts|
Substance P is a key mediator of inflammation due to immune complexes.1 This type III hypersensitivity response is an underlying event in many medical conditions, such as rheumatoid arthritis, vasculitides and systemic lupus erythematosus,2 where there is a correlation between titre of immune complexes and disease severity.
Immune complexes cause inflammation by a mechanism that involves local deposition of complexes in tissues or vessel walls. This initiates vascular permeability changes leading to edema and leucocyte extravasation, two key components of an inflammatory response. The main leucocytes involved are neutrophils. In addition, there is stimulation of macrophages, activation of complement via the classical pathway and production of reactive oxygen intermediates. The identification of Substance P as a key player in this mechanism may have significant impact on therapeutic strategies for many diseases.
Several animal models have been used to study type III hypersensitivity, the Arthus reaction being the most widely known. A model of pulmonary inflammation caused by the intrapulmonary formation of immune complexes in mice has been used to demonstrate that Substance P and C5a play pivotal roles in modulating the inflammatory response.1
Sylvestre and Ravetch3 showed with Fc-receptor (FcR)-knockout mice that FcR mediate the Arthus reaction. Despite normal inflammatory responses to other stimuli, these FcR-deficient mice had an attenuated response to immune complexes.
What was the responsible cell? A likely candidate is the mast cell. It has Fc gamma RII and Fc gamma RIII receptors, it stores many inflammatory mediators and it is found in high concentrations in the skin and around blood vessels, where it is easily accessible to circulating immune complexes. Triggering mast cells would lead to release of pre-formed mediators and would increase vascular permeability, activate complement and stimulate local adhesion and extravasation of neutrophils. Resident macrophages and neutrophils may also play a similar role in triggering a chemotactic cascade.
Bozic et al.1 also used knockout mouse technology. They disrupted the genes for the Substance P receptor (NK-1R) and for the C5a anaphylatoxin receptor (C5aR). Homozygous deletion mutants for NK-1R were apparently normal and were fertile, but when inflammation was initiated with capsaicin, which is known to induce Substance P, the knockout mice had significantly less inflammation than controls. These mice were then challenged with immune complexes formed in vivo by the injection of chicken egg albumin and rabbit antiserum to chicken egg albumin. The NK-1R-knockout mice had near complete protection from the inflammatory response. Similar results were obtained with C5a-deficient mice.
The immune-complex-mediated inflammation in wild type mice showed substantial accumulation of both Substance P and TNF-alpha in the bronchoalveolar lavage (BAL) fluid. The knockout mice had Substance P and TNF-alpha at concentrations similar to those in the wild-type mice, even though the knockout mice had no inflammation. Substance P was detectable as early as one hour, before the accumulation of neutrophils, suggesting that there was normal production of Substance P and TNF-alpha in the NK-1R-knockout mice.
The early release of Substance P may amplify subsequent inflammatory responses. Substance P has many pro-inflammatory effects, one of which is increased vascular leakage. In the model discussed here, this would lead to more antigen available to form immune complexes in lung tissue, and it would allow the delivery of complement components into the tissue where it would be fixed by the immune complexes and lead to C5a anaphylatoxin generation. Both these processes would serve to amplify the inflammatory reaction.
These findings demonstrate a link between the engagement of FcR and the humoral mediators of inflammation, showing that complement-dependent inflammation is C5aR-dependent and is downstream of immune complex release of Substance P.
In studies of rheumatoid arthritis, the human synovium has been shown to be richly innervated with Substance P immunoreactive nerve fibers, and synovial fluid has been shown to contain Substance P. The Substance P receptor is found on endothelial cells of the synovial vessels. The availability of new tachykinin antagonists may therefore prove invaluable in assessing neurogenic activity within joints. Enhanced tachykinin signalling during inflammation contributes to spinal hyperexcitability, which is the underlying mechanism for hyperalgesia. The ability to block the Substance P receptor, either by gene deletion or receptor antagonists, could exert potent anti-inflammatory analgesic effects in man.4