Collagen VI Encodes Antimicrobial Activity: Novel Innate Host Defense Properties of the Extracellular Matrix

Abdillahi, Suado M; Balvanović, Selma; Baumgarten, Maria; Mörgelin, Matthias

doi:10.1159/000335239

Cited by 17 publications

(16 citation statements)

References 45 publications

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“…Similar observations have been made for other ECM components such as collagen type VI, characterizing its antibacterial activity by membrane disruption and describing its previously unrecognized role as an innate host-defense effector molecule in connective tissues [44]. …”

Section: Discussionsupporting

confidence: 65%

Processing of Laminin α Chains Generates Peptides Involved in Wound Healing and Host Defense

Senyürek¹,

Kempf²,

Klein³

et al. 2014

J Innate Immun

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Laminins play a fundamental role in basement membrane architecture and function in human skin. The C-terminal laminin G domain-like (LG) modules of laminin α chains are modified by proteolysis to generate LG1-3 and secreted LG4-5 tandem modules. In this study, we provide evidence that skin-derived cells process and secrete biologically active peptides from the LG4-5 module of the laminin α3, α4 and α5 chain in vitro and in vivo. We show enhanced expression and processing of the LG4-5 module of laminin α3 in keratinocytes after infection and in chronic wounds in which the level of expression and further processing of the LG4-5 module correlated with the speed of wound healing. Furthermore, bacterial or host-derived proteases promote processing of laminin α3 LG4-5. On a functional level, we show that LG4-5-derived peptides play a role in wound healing. Moreover, we demonstrate that LG4-derived peptides from the α3, α4 and α5 chains have broad antimicrobial activity and possess strong chemotactic activity to mononuclear cells. Thus, the data strongly suggest a novel multifunctional role for laminin LG4-5-derived peptides in human skin and its involvement in physiological processes and pathological conditions such as inflammation, chronic wounds and skin infection.

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Section: Discussionsupporting

confidence: 65%

Processing of Laminin α Chains Generates Peptides Involved in Wound Healing and Host Defense

Senyürek¹,

Kempf²,

Klein³

et al. 2014

J Innate Immun

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“…Recently we identified this collagen as an adhesive substrate for the Gram-positive pathogens Streptococcus pyogenes and Streptococcus pneumoniae [21]. In addition, we found that collagen VI kills streptococci, implying a novel role in connective tissue innate immunity by encoding both adhesive and antimicrobial properties [22]. …”

Section: Introductionmentioning

confidence: 99%

Collagen VI Is Upregulated in COPD and Serves Both as an Adhesive Target and a Bactericidal Barrier for <b><i>Moraxella catarrhalis</i></b>

Abdillahi

Bober²,

Nordin

et al. 2015

J Innate Immun

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Moraxella catarrhalis is a Gram-negative human mucosal commensal and pathogen. It is a common cause of exacerbation in chronic obstructive pulmonary disease (COPD). During the process of infection, host colonization correlates with recognition of host molecular patterns. Importantly, in COPD patients with compromised epithelial integrity the underlying extracellular matrix is exposed and provides potential adhesive targets. Collagen VI is a ubiquitous fibrillar component in the airway mucosa and has been attributed both adhesive and killing properties against Gram-positive bacteria. However, less is known regarding Gram-negative microorganisms. Therefore, in the present study, the interaction of M. catarrhalis with collagen VI was characterized. We found that collagen VI is upregulated in the airways of COPD patients and exposed upon epithelial desquamation. Ex vivo, we inoculated airway biopsies and fibroblasts from COPD patients with M. catarrhalis. The bacteria specifically adhered to collagen VI-containing matrix fibrils. In vitro, purified collagen VI microfibrils bound to bacterial surface structures. The primary adhesion target was mapped to the collagen VI α₂-chain. Upon exposure to collagen VI, bacteria were killed by membrane destabilization in physiological conditions. These previously unknown properties of collagen VI provide novel insights into the extracellular matrix innate immunity by quickly entrapping and killing pathogen intruders.

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“…Molecular complexes between p33 and histone/gold conjugates (5 nm) were negatively stained with 0.75% uranyl formate. Specimens were subjected to transmission electron microscopy as previously described [21] and examined in a Philips/FEI CM 100 transmission electron microscope at the Core Facility for Integrated Microscopy, Panum Institute, University of Copenhagen.…”

Section: Methodsmentioning

confidence: 99%

Treatment with p33 Curtails Morbidity and Mortality in a Histone-Induced Murine Shock Model

et al. 2014

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Collateral damage caused by extracellular histones has an immediate impact on morbidity and mortality in many disease models. A significant increase in the levels of extracellular histones is seen in critically ill patients with trauma and sepsis. We showed that histones are released from necrotic cells in patients with invasive skin infections. Under in vitro conditions, endogenous p33, an endothelial surface protein also known as the gC1q receptor, interacts with histones released from damaged endothelial cells. Functional analyses have revealed that recombinantly expressed p33 completely neutralizes the harmful features of histones, i.e. hemolysis of erythrocytes, lysis of endothelial cells and platelet aggregation. We also noted that mice treated with a sublethal dose of histones developed severe signs of hemolysis, thrombocytopenia and lung tissue damage already 10 min after inoculation. These complications were fully counteracted when p33 was administered together with the histones. Moreover, application of p33 significantly improved survival in mice receiving an otherwise lethal dose of histones. Together, our data suggest that treatment with p33 is a promising therapeutic approach in severe infectious diseases.

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Collagen VI Encodes Antimicrobial Activity: Novel Innate Host Defense Properties of the Extracellular Matrix

Cited by 17 publications

References 45 publications

Processing of Laminin α Chains Generates Peptides Involved in Wound Healing and Host Defense

Processing of Laminin α Chains Generates Peptides Involved in Wound Healing and Host Defense

Collagen VI Is Upregulated in COPD and Serves Both as an Adhesive Target and a Bactericidal Barrier for <b><i>Moraxella catarrhalis</i></b>

Treatment with p33 Curtails Morbidity and Mortality in a Histone-Induced Murine Shock Model

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