Divergent functions for airway epithelial matrix metalloproteinase 7 and retinoic acid in experimental asthma

Goswami, Sangeeta; Angkasekwinai, Pornpimon; Shan, Ming; Greenlee, Kendra J.; Barranco, Wade T.; Polikepahad, Sumanth; Seryshev, Alexander; Li, Song; Redding, D.; Singh, Bhupinder; Sur, Sanjiv; Woodruff, Prescott G.; Dong, Chen; Corry, David B.; Kheradmand, Farrah

doi:10.1038/ni.1719

Cited by 106 publications

(104 citation statements)

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“…Matrilysin/matrix metalloproteinase (MMP) 7 is an epithelial MMP that is induced in response to injury, infection, or allergen challenge (6)(7)(8). We reported that, in response to lung or colon injury, transepithelial migration of neutrophils is halted in Mmp7 2/2 mice (9, 10).…”

mentioning

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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mentioning

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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“…In complete Aspergillus allergen-immunized mice model, epithelial metalloproteinase 7 (MMP7) activated IL-25 to promote Th2 cells differentiation, but inhibited RALDH1 and thus Treg development (61). Therefore, MMP7 Ϫ/Ϫ mice showed higher RALDH1 expression, lower IL-4 and IL-5 in bronchoalveolar fluid, and dampened airway hyperreactivity.…”

Section: Ra Regulates Allergy Through Tregsmentioning

confidence: 99%

Leukocyte Homing, Fate, and Function Are Controlled by Retinoic Acid

Guo

Brown

Ortiz

et al. 2015

Physiological Reviews

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Although vitamin A was recognized as an "anti-infective vitamin" over 90 years ago, the mechanism of how vitamin A regulates immunity is only beginning to be understood. Early studies which focused on the immune responses in vitamin A-deficient (VAD) animals clearly demonstrated compromised immunity and consequently increased susceptibility to infectious disease. The active form of vitamin A, retinoic acid (RA), has been shown to have a profound impact on the homing and differentiation of leukocytes. Both pharmacological and genetic approaches have been applied to the understanding of how RA regulates the development and differentiation of various immune cell subsets, and how RA influences the development of immunity versus tolerance. These studies clearly show that RA profoundly impacts on cell-and humoralmediated immunity. In this review, the early findings on the complex relationship between VAD and immunity are discussed as well as vitamin A metabolism and signaling within hematopoietic cells. Particular attention is focused on how RA impacts on T-cell lineage commitment and plasticity in various diseases.

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“…29 Recently it has been shown that RALDH-1, the ratelimiting enzyme that converts retinaldehyde to RA, was up-regulated in response to allergic stimulation in the airway epithelium, which indicates a possible site for RA production in the lung. 60 Further, liposome-mediated delivery of RA 1 hour before immunization resulted in attenuated lung inflammation compared with control mice that received empty liposomes. Similarly, Citral, an inhibitor of RALDH-1, resulted in reduced synthesis of RA and fewer Tregs in the lung.…”

Section: Tregs In Allergic Inflammationmentioning

confidence: 99%