Tissue Inhibitor of Metalloproteinase 1 Regulates Resistance to Infection

Abstract

Tissue inhibitor of metalloproteinase 1 (TIMP-1)-deficient mice are resistant to Pseudomonas aeruginosa corneal infections. Corneas healed completely in TIMP-1-deficient mice, and infections were cleared faster in TIMP-1-deficient mice than in wild-type littermates. Genetic suppression studies using matrix metalloproteinase (MMP)-deficient mice showed that MMP-9, MMP-3, and MMP-7 but not MMP-2 or MMP-12 are needed for resistance. Increased resistance was also seen during pulmonary infections. These results identify a novel pathway regulating infection resistance.Twenty-five matrix metalloproteinases (MMPs) comprise the major extracellular matrix-degrading activities in mammals. They can remodel matrix during development, tumor metastasis, and cell migration but have nonmatrix substrates as well. MMPs are inhibited posttranslationally by four tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2, TIMP-3, and TIMP-4) and by ␣ 2 -macroglobulin (33).Many correlative studies have suggested that MMP production was associated with inflammation and that MMP inhibition had an anti-inflammatory effect (3-5, 21, 26, 29). More recently, studies with MMP mutant mice have confirmed that MMPs play an important role in promoting inflammation and immunity: overexpression of MMP-1 in lungs promotes a spontaneous emphysema-like response (6), MMP-12 loss attenuates macrophage migration and lung damage caused by cigarette smoke (27), MMP-7 participates in proteolytic activation of antibacterial defensins by epithelial cells (32) and chemoattraction of inflammatory cells to the lung (16), and MMP-3 loss diminishes T-cell-dependent delayed type hypersensitivity responses, while the loss of MMP-9 delays the resolution of those responses (30). TIMP expression has also been associated with a variety of infectious and noninfectious inflammatory conditions, including those affecting the eye (12, 14, 34), and TIMP-3 regulates tumor necrosis factor alpha (TNF-␣) production (18). Collectively, these data highlight varied and complex roles for components of the TIMP-MMP axis during immune and inflammatory responses; however, TIMPs have not been directly shown to regulate responses to infection. To study the role of TIMP-1 in inflammation and immunity and its possible involvement in other physiological processes, mice deficient in TIMP-1 were generated and evaluated for responses during corneal and pulmonary infections with Pseudomonas aeruginosa.Preparation of Timp1 mutant mice. A replacement vector (Fig. 1A) targeted to the Timp1 locus in embryonic stem (ES) cells (Fig. 1B) produced a null allele in mice (Fig. 1C). The replacement vector included a 3.3-kb NdeI to HindIII 5Ј arm; a 21-mer oligonucleotide (5Ј-CTGATCAGCTGACTCGAG G-3Ј) at an EcoRV site in the third coding exon that abolished the EcoRV site generating BamHI, BglII, and XhoI sites; a G418 drug resistance cassette at the XhoI site; and a TK marker. Electroporated ES clones were screened by Southern blot analysis with a 1,400-nucleotide HindIII-NdeI Timp1 5Ј fragment as a probe. Mu...

Matrix Metalloproteinases in Lung: Multiple, Multifarious, and Multifaceted

“…To identify which MMP is responsible for the increased resistance, researchers created double null mice by crossing TIMP1 null mice with mice deficient in MMPs known to be inhibited by TIMP1 in vivo, including MMP2, MMP3, MMP7, MMP9, and MMP12. MMP9/TIMP1 double null mice completely lose their resistance to infection, and MMP3/TIMP1 and MMP7/TIMP1 mice have decreased resistance, while MMP2 and MMP12 do not play a role (140). Although these studies did not directly examine the mechanism involved in the protective effect of MMPs in infection with Pseudomonas, other studies have shown that shedding of syndecan1 from airway epithelial cells, which is dependent on cleavage by MMP7, is critical for defense against this organism (169,210).…”

Matrix metalloproteinases and the regulation of tissue remodelling

“…The same MMP can have different roles in different conditions. For example, MMP9 contributes to inflammation in mouse models of stroke, heart attack, Alzheimer's disease, some aspects of asthma and other lung inflammatory conditions, aortic aneurysms and autoimmune encephalomyelitis 9,[106][107][108][109][110] ; however, it functions as an anti-inflammatory agent in models of inflammatory skin and kidney diseases 89,111,112 . Current data indicate that MMP12 contributes to emphysema 113,114 , whereas MMP3 and MMP9 contribute to skin inflammatory conditions 89,115 .…”

MyD88-dependent changes in the pulmonary transcriptome after infection withChlamydia pneumoniae

“…This protein has been recently described to enhance pathology during infections. For instance, TIMP1-deficient mice are resistant to Pseudomonas aeruginosa corneal infection and show reduced lethality on pulmonary infection with the same microorganism (36). Therefore, the function of timp1 may be important for the elucidation of Analysis of overrepresentation of medical subject heading (MeSH) terms for transcripts corresponding to clusters A-D. A high z-score indicates a significant overrepresentation of a category.…”