Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, -8, and -13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx.

@article{Dean2008MacrophagespecificM,
  title={Macrophage-specific metalloelastase (MMP-12) truncates and inactivates ELR+ CXC chemokines and generates CCL2, -7, -8, and -13 antagonists: potential role of the macrophage in terminating polymorphonuclear leukocyte influx.},
  author={Richard A. Dean and Jennifer H. Cox and Caroline L. Bellac and Alain Doucet and Amanda E Starr and Christopher M. Overall},
  journal={Blood},
  year={2008},
  volume={112 8},
  pages={
          3455-64
        }
}
Through the activity of macrophage-specific matrix metalloproteinase-12 (MMP-12), we found that macrophages dampen the lipopolysaccharide (LPS)-induced influx of polymorphonuclear leukocytes (PMNs)-thus providing a new mechanism for the termination of PMN recruitment in acute inflammation. MMP-12 specifically cleaves human ELR(+) CXC chemokines (CXCL1, -2, -3, -5, and -8) at E-LR, the critical receptor-binding motif or, for CXCL6, carboxyl-terminal to it. Murine (m) MMP-12 also cleaves mCXCL1… 
View on PubMed
bloodjournal.org
233 Citations
Highly Influential Citations
11
Background Citations
90
Methods Citations
3
Results Citations
3

Figures from this paper

233 Citations

Biochemical Characterization and N-terminomics Analysis of Leukolysin, the Membrane-type 6 Matrix Metalloprotease (MMP25)

Biochemically characterized MT6-MMP, profiled its tissue inhibitor of metalloproteinase inhibitory spectrum, performed degradomics analyses, and screened 26 chemokines for cleavage using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry to indicate a role for clearance of apoptotic neutrophils.

New insights into the substrate specificity of macrophage elastase MMP-12

Four series of fluorogenic peptide substrates were synthesized based on the sequences of MMP-12 cleavage sites in its known substrates, indicating that the C-terminal hemopexin domain influences substrate binding and/or catalysis.

Emergence of a metalloproteinase / phospholipase A2 axis of systemic inflammation.

It is postulated that PLA2 activation is induced by chemokines, whose ability to signal inflammation is regulated in a tissue-specific fashion by MMPs, and genetic and pharmacologically induced MMP-deficiencies can be expected to perturb PLA2-mediated inflammatory mechanisms.

Investigation of the Production, Distribution, and Trafficking of MMP-9 in Classically Activated Macrophages

A functional contribution of stable MTs in the enhanced trafficking of MMP-9 extracellularly is demonstrated, and it is shown that heterogeneity exists in macrophage cell populations with respect to M MP-9 production.

Macrophage matrix metalloproteinase-12 dampens inflammation and neutrophil influx in arthritis.

Moonlighting matrix metalloproteinase substrates: Enhancement of proinflammatory functions of extracellular tyrosyl-tRNA synthetase upon cleavage

The proinflammatory activity of YRS is enhanced by MMP cleavage, which is suggested to form a feed-forward mechanism to promote inflammation.

Biochemical Analysis of Matrix Metalloproteinase Activation of Chemokines CCL15 and CCL23 and Increased Glycosaminoglycan Binding of CCL16*

This study reveals for the first time that MMPs activate the long amino-terminal chemokines CCL15 and CCL23 to potent forms that have potential to increase monocyte recruitment during inflammation.

C-terminal truncation of IFN-γ inhibits proinflammatory macrophage responses and is deficient in autoimmune disease

It is shown that M MP12 expression is reduced in patients with SLE and that MMP12 post-translationally truncates IFN-y, inhibiting its function and affecting pathogenesis of mouse models of peritonitis, S LE and rheumatoid arthritis.

A CCL chemokine-derived peptide (CDIP-2) exerts anti-inflammatory activity via CCR1, CCR2 and CCR3 chemokine receptors: Implications as a potential therapeutic treatment of asthma.

A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity

It is shown that after macrophage secretion, MMP-12 is transported into virus-infected cells, and it is suggested that inhibiting extracellular M MP-12 could be a new avenue for the development of antiviral treatments.
...

References

SHOWING 1-10 OF 53 REFERENCES

Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo.

It is proposed that MMPs have an important role in modulating inflammatory and immune responses by processing chemokines in wound healing and in disease.

Matrix Metalloproteinase Activity Inactivates the CXC Chemokine Stromal Cell-derived Factor-1*

The N-terminal processing of the CXC chemokines stromal cell-derived factor (SDF)-1α and β by MMP-2 is reported, suggesting that MMPs may be important regulatory proteases in attenuating SDF-1 function and point to a deep convergence of two important networks, chemokine and M MPs, to regulate leukocytic activity in vivo.

Matrix Metalloproteinase Processing of CXCL11/I-TAC Results in Loss of Chemoattractant Activity and Altered Glycosaminoglycan Binding*

Results reveal potential new roles in down-regulating Th1 lymphocyte chemoattraction through MMP processing of CXCL11 and highlight an unexpected site for receptor interaction and that the carboxyl terminus is critical for glycosaminoglycan binding, an essential function for the formation of chemokine gradients in vivo.

Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-alpha and leaves RANTES and MCP-2 intact.

A better understanding of regulator (IL-8) and effector molecules (gelatinase B) of neutrophils and of mechanisms underlying leukocytosis, shock syndromes, and stem cell mobilization by IL-8 is led to.

LPS Responsiveness and Neutrophil Chemotaxis In Vivo Require PMN MMP-8 Activity

The identification of matrix metalloproteinase (MMP)-8, the polymorphonuclear (PMN) leukocyte collagenase, as a critical mediator initiating lipopolysaccharide (LPS)-responsiveness in vivo identifies MMP-8 as a key mediator in the regulation of innate immunity.

Differential usage of the CXC chemokine receptors 1 and 2 by interleukin-8, granulocyte chemotactic protein-2 and epithelial-cell-derived neutrophil attractant-78.

The differential receptor usage of the structurally related ELR+ CXC chemokines GCP-2 and ENA-78 is indicative of a different role in inflammatory reactions.

Macrophage metalloelastase mediates acute cigarette smoke-induced inflammation via tumor necrosis factor-alpha release.

Findings suggest that, acutely, MMP-12 mediates smoke-induced inflammation by releasing TNF-alpha from macrophages, with subsequent endothelial activation, neutrophil influx, and proteolytic matrix breakdown caused by neutrophile-derived proteases.

Role of resident peritoneal macrophages and mast cells in chemokine production and neutrophil migration in acute inflammation: evidence for an inhibitory loop involving endogenous IL-10.

A stimulus-dependent role of resident MCs inChemokine production and the existence of a regulatory loop between endogenous IL-10 and the chemokine-mediated cellular component of acute inflammation are proposed.

Proteolytic processing of SDF-1α reveals a change in receptor specificity mediating HIV-associated neurodegeneration

These studies reveal additive neuropathogenic properties exerted by a proteolytically cleaved chemokine as consequences of a change in receptor specificity, culminating in neurodegeneration.

Macrophage elastase (MMP-12): a pro-inflammatory mediator?

The instillation of a recombinant form of human MMP-12 in mouse airways induced a severe inflammatory cell recruitment characterized by an early accumulation of neutrophils correlated with an increase in proinflammatory cytokines and in gelatinases and indicated that the model could mimic some of the inflammatory features observed in COPD patients and could be used for the pharmacological evaluation of new anti-inflammatory treatment.
...