Matrix Metalloproteinase-8 Plays a Pivotal Role in Neuroinflammation by Modulating TNF-α Activation

Lee, Eun Jung; Han, Jeong Eun; Woo, Moon Sook; Shin, Jeong-Ah; Park, Eun Mi; Kang, Jihee Lee; Moon, Pyong Gon; Baek, Moon Chang; Son, Woo Sung; Ko, Young Tag; Choi, Ji Woong; Kim, Hee Sun

doi:10.4049/jimmunol.1303240

Cited by 65 publications

(61 citation statements)

References 56 publications

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“…IL-8 is a macrophage-generated and secreted inflammatory chemokine that binds Toll-like receptors and plays a role in innate immune system responses [37, 38]. The matrix metalloproteinase MMP-8, when aberrantly produced by microglial cells, facilitates neuroinflammatory responses through its effects on TNFα [39]. Demonstrating effects on the expression of these genes could prove relevant to AD, a disorder that features neuroinflammation, elevated TNFα levels, reduced TREM2 levels [36, 40], and an increased risk for individuals that carry loss-of-function TREM2 sequence variants [2].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Lysates Induce Inflammation and Alzheimer's Disease-Relevant Changes in Microglial and Neuronal Cells

Wilkins

Carl

Weber

et al. 2015

JAD

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Neuroinflammation occurs in AD. While AD genetic studies implicate inflammation-relevant genes and fibrillar amyloid β protein promotes inflammation, our understanding of AD neuroinflammation nevertheless remains incomplete. In this study we hypothesized damage-associated molecular pattern (DAMP) molecules arising from mitochondria, intracellular organelles that resemble bacteria, could contribute to AD neuroinflammation. To preliminarily test this possibility, we exposed neuronal and microglial cell lines to enriched mitochondrial lysates. BV2 microglial cells treated with mitochondrial lysates showed decreased TREM2 mRNA, increased TNFα mRNA, increased MMP-8 mRNA, increased IL-8 mRNA, redistribution of NFκB to the nucleus, and increased p38 MAPK phosphorylation. SH-SY5Y neuronal cells treated with mitochondrial lysates showed increased TNFα mRNA, increased NFκB protein, decreased IκBα protein, increased AβPP mRNA, and increased AβPP protein. Enriched mitochondrial lysates from SH-SY5Y cells lacking detectable mitochondrial DNA (ρ0 cells) failed to induce any of these changes, while mtDNA obtained directly from mitochondria (but not PCR-amplified mtDNA) increased BV2 cell TNFα mRNA. These results indicate at least one mitochondrial-derived DAMP molecule, mtDNA, can induce inflammatory changes in microglial and neuronal cell lines. Our data are consistent with the hypothesis that a mitochondrial-derived DAMP molecule or molecules could contribute to AD neuroinflammation.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Lysates Induce Inflammation and Alzheimer's Disease-Relevant Changes in Microglial and Neuronal Cells

Wilkins

Carl

Weber

et al. 2015

JAD

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“…MMP8 was also characterized as a protease responsible for SIRP␣ proteolysis in primary neutrophils (13). However, this may not be the case because the inhibitor used in those experiments was shown to be promiscuous, inhibiting many MMPs and ADAM proteases (12,31). Using specific inhibitors and RNAi, we determined that ADAM10 was involved in SIRP␣ proteolysis in epithelial and monocytic cells.…”

Section: Discussionmentioning

confidence: 99%

Cleavage of Signal Regulatory Protein α (SIRPα) Enhances Inflammatory Signaling

Londino

Gulick

Isenberg

et al. 2015

Journal of Biological Chemistry

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Signal regulatory protein ␣ (SIRP␣) is a membrane glycoprotein immunoreceptor abundant in cells of monocyte lineage. SIRP␣ ligation by a broadly expressed transmembrane protein, CD47, results in phosphorylation of the cytoplasmic immunoreceptor tyrosine-based inhibitory motifs, resulting in the inhibition of NF-B signaling in macrophages. Here we observed that proteolysis of SIRP␣ during inflammation is regulated by a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), resulting in the generation of a membrane-associated cleavage fragment in both THP-1 monocytes and human lung epithelia. We mapped a charge-dependent putative cleavage site near the membrane-proximal domain necessary for ADAM10-mediated cleavage. In addition, a secondary proteolytic cleavage within the membrane-associated SIRP␣ fragment by ␥-secretase was identified. Ectopic expression of a SIRP␣ mutant plasmid encoding a proteolytically resistant form in HeLa cells inhibited activation of the NF-B pathway and suppressed STAT1 phosphorylation in response to TNF␣ to a greater extent than expression of wild-type SIRP␣. Conversely, overexpression of plasmids encoding the proteolytically cleaved SIRP␣ fragments in cells resulted in enhanced STAT-1 and NF-B pathway activation. Thus, the data suggest that combinatorial actions of ADAM10 and ␥-secretase on SIRP␣ cleavage promote inflammatory signaling.Inhibitory receptors including signal regulatory protein ␣ (SIRP␣), 2 CD33, SIGLECs (sialic acid-binding immunoglobulin-type lectins), CD66a, PD-1, CD31, PILRa (paired immunoglobin-like type 2 receptor ␣), CMRF35H, gp49B1, PECAM1, and others have been demonstrated to suppress the initiation of inflammatory signaling and contribute to the resolution of inflammation after infection (1, 2). SIRP␣ is membrane glycoprotein immunoreceptor that is expressed mainly in myeloid and neuronal cells (3). Ligation of SIRP␣ results in phosphorylation of the cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which recruit and activate SH2 domain-containing phosphotyrosine phosphatases SHP-1 and SHP-2 (4). SIRP␣ signaling results in reduced macrophage migration and phagocytosis and inhibition of NF-B signaling with reduction of release of NF-B-dependent cytokines in macrophages (5, 6). Phosphorylation of SIRP␣ ITIM domains also enhances JAK/STAT activation and NADPH oxidase expression and activity (7). Thus, SIRP␣ serves as an important modulator of the host adaptive immune response. Proteolysis and release of the SIRP␣ NH 2 -terminal domain has been demonstrated in primary cultured neurons, melanoma cells, and macrophage cell lines. Cleavage of murine SIRP␣ through an MMP inhibitor-sensitive pathway was first observed in cultured cells engineered to express both SIRP␣ and an active form of Ras (8). In these cells, blocking SIRP␣ proteolysis resulted in inhibited cell migration, cell spreading, and cytoskeletal reorganization. In addition, SIRP␣ was shown to regulate synaptic activity through activation of MMP inhibitor-sensitive prote...

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“…Recent studies seem to provide some possible clues for ADAM17 regulation in microglia. Microglial reaction and TNFa expression can be attenuated by ADAM17 inhibitor through p38-MAPK/ ERK and NFjB signaling (Lee et al 2014). Besides, a serine proteinase, inactive Rhomboid 2 (iRhom2), emerged as a molecule that controls the maturation and function of ADAM17 and TNFa secretion, especially in microglia (Li et al 2015).…”

Section: Adam17 Activity Regulation-beneficial or Harmful In Ad?mentioning

confidence: 98%

The Distinct Role of ADAM17 in APP Proteolysis and Microglial Activation Related to Alzheimer’s Disease

Meng

Wang

2015

Cell Mol Neurobiol

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Alzheimer's disease (AD) is a progressive neurodegenerative disease with the symptom of cognitive impairment. The deposition of amyloid β (Aβ) peptide is believed to be the primary cause to neuronal dystrophy and eventually dementia. Aβ is the proteolytic product from its precursor amyloid precursor protein (APP) by β- and γ- secretase. An optional cleavage by α-secretase happens inside the Aβ domain. ADAM17 is supposed to be the regulated α-secretase of APP. Enhanced activity of ADAM17 leads to the increasing secretion of neuroprotective soluble APP α fragment and reduction of Aβ generation, which may be benefit to the disease. ADAM17 is then considered the potential therapeutic target for AD. Microglia activation and neuroinflammation is another important event in AD pathogenesis. Interestingly, ADAM17 also participates in the cleavage of many other membrane-bound proteins, especially some inflammatory factors related to microglia activation. The facilitating role of ADAM17 in inflammation and further neuronal damage has also been illustrated. In results, the activation of ADAM17 as the solution to AD may be a tricky task. The comprehensive consideration and evaluation has to be carried out carefully before the final treatment. In the present review, the distinct role of ADAM17 in AD-related APP shedding and neuroinflammatory microglial activation will be carefully discussed.

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Matrix Metalloproteinase-8 Plays a Pivotal Role in Neuroinflammation by Modulating TNF-α Activation

Cited by 65 publications

References 56 publications

Mitochondrial Lysates Induce Inflammation and Alzheimer's Disease-Relevant Changes in Microglial and Neuronal Cells

Mitochondrial Lysates Induce Inflammation and Alzheimer's Disease-Relevant Changes in Microglial and Neuronal Cells

Cleavage of Signal Regulatory Protein α (SIRPα) Enhances Inflammatory Signaling

The Distinct Role of ADAM17 in APP Proteolysis and Microglial Activation Related to Alzheimer’s Disease

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