Regulation of innate immune response to infection by TIMP-1

The roles of tissue inhibitors of matrix metalloproteinases (TIMPs) and matrix metalloproteinases (MMPs) as regulators of the immune response are unclear. TIMPs inhibit the ability of MMPs to digest the extracellular matrix during normal and pathogenic processes. Timp1−/− mice exhibit increased resistance to corneal infection with Pseudomonas aeruginosa (PA) relative to wild-type mice. Timp1−/− mice had 500 fold fewer corneal bacteria than wild-type mice 24 hours after infection. Timp2 −/− mice do not exhibit infection resistance. This suggests that loss of TIMP-1 may have some therapeutic potential against infection dependent diseases such as cystic fibrosis (CF). I explored the mechanisms behind and the therapeutic potential of TIMP-1 dependent resistance to infection in PA infected eyes and lungs. It has been previously established that increased resistance to infection in Timp1−/− animals is dependent upon MMP inhibitory activity and the complement component of the innate immune response. Suppression studies in animals deficient in both TIMP-1 as well as a target MMP suggests that the unregulated activities of MMP-3, MMP-7 and MMP-9 are required for TIMP-1 dependent resistance to infection. In the lungs, acute pulmonary infections in Timp1 −/− animals established pulmonary TIMP-1 dependent resistance to infection. Pulmonary TIMP-1 dependent resistance to infection is also complement dependent but suppression analysis identified lesser roles for MMP-7 and MMP-9. These results suggest that a TIMP-1 antagonist may have some therapeutic potential. Phage display panning of random peptide libraries over the TIMP-1 C-connector loop identified three possible TIMP-1 antagonist peptides. Collaborative testing of the candidates for their ability to inhibit TIMP-1 identified no TIMP-1 antagonist. Exploration of the therapeutic potential of TIMP-1 in CF by acute pulmonary infections in Timp1−/− animals bearing the cystic fibrosis transmembrane regulator (Cftr ) mutation suggests no resistance to acute pulmonary infections in the absence of TIMP-1. Although this suggests that TIMP-1 may have no therapeutic potential in CF, this mouse model and this infection method are not ideal for studying CF. More mild and natural infection methods may identify TIMP-1 as a therapeutic target for pulmonary disease.