Tissue Inhibitor of Metalloproteinases 3 Regulates Resolution of Inflammation following Acute Lung Injury

Gill, Sean E.; Huizar, Isham; Bench, Eli M.; Sussman, Samuel W.; Wang, Ying; Khokha, Rama; Parks, William C.

doi:10.2353/ajpath.2010.090158

Cited by 70 publications

(74 citation statements)

References 38 publications

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“…Recently, we demonstrated that the absence of TIMP-3 resulted in increased neutrophil accumulation in the lungs after bleomycin-induced lung injury, ultimately leading to an impaired resolution of inflammation (23). In this study, we confirm the role of TIMP-3 in regulating inflammation after lung injury, and identify TIMP-3 as a key moderator of macrophage proinflammatory (M1) polarization.…”

supporting

confidence: 73%

Tissue Inhibitor of Metalloproteinases–3 Moderates the Proinflammatory Status of Macrophages

Gill

Gharib

Bench

et al. 2013

Am J Respir Cell Mol Biol

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Tissue inhibitor of metalloproteinases-3 (TIMP-3) has emerged as a key mediator of inflammation. Recently, we reported that the resolution of inflammation is impaired in Timp3 2/2 mice after bleomycininduced lung injury. Here, we demonstrate that after LPS instillation (another model of acute lung injury), Timp32/2 mice demonstrate enhanced and persistent neutrophilia, increased numbers of infiltrated macrophages, and delayed weight gain, compared with wild-type (WT) mice. Because macrophages possess broad immune functions and can differentiate into cells that either stimulate inflammation (M1 macrophages) or are immunosuppressive (M2 macrophages), we examined whether TIMP-3 influences macrophage polarization. Comparisons of the global gene expression of unstimulated or LPS-stimulated bone marrow-derived macrophages (BMDMs) from WT and Timp3 2/2 mice revealed that Timp3 2/2 BMDMs exhibited an increased expression of genes associated with proinflammatory (M1) macrophages, including Il6, Il12, Nos2, and Ccl2. Microarray analyses also revealed a baseline difference in gene expression between WT and Timp3 2/2 BMDMs, suggesting altered macrophage differentiation. Furthermore, the treatment of Timp3 2/2 BMDMs with recombinant TIMP-3 rescued this altered gene expression. We also examined macrophage function, and found that Timp3 2/2 M1 cells exhibit significantly more neutrophil chemotactic activity and significantly less soluble Fas ligand-induced caspase-3/7 activity, a marker of apoptosis, compared with WT M1 cells. Macrophage differentiation into immunosuppressive M2 cells is mediated by exposure to IL-4/IL-13, and we found that Timp3 2/2 M2 macrophages demonstrated a lower expression of genes associated with an anti-inflammatory phenotype, compared with WT M2 cells. Collectively, these findings indicate that TIMP-3 functions to moderate the differentiation of macrophages into proinflammatory (M1) cells.Keywords: resolution of inflammation; macrophage; metalloproteinase; lung injury Several immunosuppressive mechanisms have evolved to ensure that acute, generally beneficial inflammation does not progress to chronic, destructive inflammation. Beyond reversal of the initiating event (e.g., bacterial clearance and wound closure), active host processes, such as the release of the anti-inflammatory cytokines IL-4, IL-10, and IL-13, among other processes (1), actively repress the proinflammatory properties of various cell types. Macrophages, through their ability to clear neutrophils and release anti-inflammatory cytokines, are thought to be important in the resolution of inflammation (2).Generally speaking, macrophages are key effectors promoting the shift from a proinflammatory to an anti-inflammatory environment, and can be broadly classified into two groups: classically activated (M1) and alternatively activated (M2) macrophages, which can be further subdivided into specialized M2 groups (3). M1 macrophages are induced by proinflammatory Th1 cytokines, such as IFN-g, and are characterized by the production of proinfl...

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supporting

confidence: 73%

Tissue Inhibitor of Metalloproteinases–3 Moderates the Proinflammatory Status of Macrophages

Gill

Gharib

Bench

et al. 2013

Am J Respir Cell Mol Biol

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“…23 Loss of TIMPs would be expected to lead to enhanced matrix proteolysis; however, TIMP3 knockout mice demonstrated enhanced fibrosis after bleomycin associated with persistent neutrophil influx. 27 Mice lacking TIMP1 have similar severity of fibrosis but greater neutrophilic inflammation compared with wild-type mice after bleomycin injury. 28 These studies and others now demonstrate that the MMPs and TIMPs influence several cellular processes, including proliferation, survival, and inflammation, that directly or indirectly influence myofibroblast activation and ECM turnover.…”

Section: Composition Of the Extracellular Matrix In Fibrosismentioning

confidence: 98%

Mechanisms of Lung Fibrosis Resolution

Glasser

Hagood

Wong

et al. 2016

The American Journal of Pathology

112

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“…, and Sdc1 2/2 mice (all C57Bl/6; near equal mix of females and males; 8 weeks old) were intubated with 2 3 10 9 CFU live Pseudomonas aeruginosa (PAO1) or bleomycin (4 U/kg), as previously described (12,13). Mice were killed at the indicated times, and lungs were either lavaged twice with PBS (1 ml/lavage) or infused with optical cutting temperature compound (VWR, Batavia, IL).…”

Section: /2mentioning

confidence: 99%

Shedding of Syndecan-1/CXCL1 Complexes by Matrix Metalloproteinase 7 Functions as an Epithelial Checkpoint of Neutrophil Activation

Gill

Nadler

et al. 2016

Am J Respir Cell Mol Biol

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Although neutrophils play critical roles in innate immunity, in excess these cells cause severe tissue damage. Thus, neutrophil activation must be tightly regulated to prevent indiscriminant damage. Previously, we reported that mice lacking matrix metalloproteinase (MMP) 7 are protected from lung injury owing to markedly impaired neutrophil movement from the interstitium into mucosal lumenal spaces. This phenotype resulted from a lack of MMP7 shedding of syndecan-1, a heparan sulfate proteoglycan that carries the neutrophil chemokine CXCL1 as cargo. Here, we assessed if shedding syndecan-1/CXCL1 complexes affects neutrophil activation. Whereas injured monolayers of wild-type alveolar type II cells potently stimulated neutrophil activation, as gauged by release of myeloperoxidase, cells from Mmp7 2/2 or syndecan-1-null (Sdc1 2/2 ) mice or human cells with MMP7 knockdown did not. In vivo, we observed reduced myeloperoxidase release relative to neutrophil numbers in bleomycin-injured Mmp7 2/2 and Sdc1 2/2 mice. Furthermore, we determined that soluble syndecan-1 directly stimulated neutrophil activation in the absence of cellular damage. These data indicate that MMP7 shedding of syndecan-1/CXCL1 complexes functions as a checkpoint that restricts neutrophil activation at sites of epithelial injury.

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Tissue Inhibitor of Metalloproteinases 3 Regulates Resolution of Inflammation following Acute Lung Injury

Cited by 70 publications

References 38 publications

Tissue Inhibitor of Metalloproteinases–3 Moderates the Proinflammatory Status of Macrophages

Tissue Inhibitor of Metalloproteinases–3 Moderates the Proinflammatory Status of Macrophages

Mechanisms of Lung Fibrosis Resolution

Shedding of Syndecan-1/CXCL1 Complexes by Matrix Metalloproteinase 7 Functions as an Epithelial Checkpoint of Neutrophil Activation

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