H. Herwald | Lund University (original) (raw)

Papers by H. Herwald

The Biochemical journal, Jan 27, 2015

The human host-defense peptide LL-37 not only displays antimicrobial activity but also immune mod... more The human host-defense peptide LL-37 not only displays antimicrobial activity but also immune modulating properties that trigger intracellular signaling events in host cells. Since the cytolytic activity of high LL-37 concentrations affects cell viability, the function of LL-37 requires tight regulation. Eukaryotic cells therefore benefit from protective measures to prevent harmful effects of LL-37. p33, also known as globular C1q receptor, is reported to act as an LL-37 antagonist by binding the peptide thereby reducing its cytotoxic activity. In this report, we show that high levels of endogenous p33 correlate with an increased viability in human cells treated with LL-37. Sub-cellular localization analysis showed p33 distribution at the mitochondria, the plasma membrane and in the cytosol. Strikingly, cytosolic over-expression of p33 significantly antagonized detrimental effects of LL-37 on cell fitness, while the reverse effect was observed by siRNA-induced down-regulation of p33...

BEHRENDT:MATRIX PROTEASES O-BK, 2012

Journal of innate immunity, 2015

Thrombosis and haemostasis, 2014

Early diagnosis of severe infectious diseases is essential for timely implementation of lifesavin... more Early diagnosis of severe infectious diseases is essential for timely implementation of lifesaving therapies. In a search for novel biomarkers in sepsis diagnosis we focused on polymorphonuclear neutrophils (PMNs). Notably, PMNs have their protein cargo readily stored in granules and following systemic stimulation, an immediate increase of neutrophil-borne proteins can be observed into the circulation of sepsis patients. We applied a combination of mass spectrometry (MS) based approaches, LC-MS/MS and selected reaction monitoring (SRM), to characterise and quantify the neutrophil proteome in healthy or disease conditions. With this approach we identified a neutrophil-derived protein abundance pattern in blood plasma consisting of 20 proteins that can be used as a protein signature for severe infectious diseases. Our results also show that SRM is highly sensitive, specific, and reproducible and, thus, a promising technology to study a complex, dynamic and multifactorial disease such ...

Journal of innate immunity, 2014

The Biochemical journal, Jan 15, 1997

H-kininogen (high-molecular-mass kininogen, HK) is the precursor of the vasoactive peptide hormon... more H-kininogen (high-molecular-mass kininogen, HK) is the precursor of the vasoactive peptide hormone bradykinin (BK). Previous work has demonstrated that HK binds to Streptococcus pyogenes through M-proteins, fibrous surface proteins and important virulence factors of these bacteria. Here we find that M-protein-expressing bacteria absorb HK from human plasma. The HK bound to the bacteria was found to be cleaved, and analysis of the degradation pattern suggested that the cleavage of HK at the bacterial surface is associated with the release of BK. Moreover, addition of activated plasma prekallikrein to bacteria preincubated with human plasma, resulted in BK release. This mechanism, by which a potent vasoactive and proinflammatory peptide is generated at the site of infection, should influence the host-parasite relationship during S. pyogenes infections.

The Journal of biological chemistry, Jan 5, 1993

Prekallikrein, a glycoprotein involved in contact phase activation, circulates in plasma in the f... more Prekallikrein, a glycoprotein involved in contact phase activation, circulates in plasma in the form of a binary complex with high molecular weight kininogen (H-kininogen). The binding to H-kininogen is mediated by the prekallikrein heavy chain consisting of four repetitive domains, A1-A4. To define more precisely the region(s) involved in kininogen binding, we have employed an affinity cross-linking strategy with a synthetic peptide of 31 residues which mimics the prekallikrein binding site of H-kininogen. Cross-linking of the radiolabeled peptide to (pre)kallikrein revealed a binding segment in the NH2-terminal portion of the prekallikrein heavy chain; another binding segment was located in the COOH-terminal part of the heavy chain. The latter binding segment is harbored by a previously identified fragment of the kallikrein heavy chain involved in H-kininogen binding (Page, J.D., and Colman, R.W. (1991) J. Biol. Chem. 266, 8143-8148). Chemical cleavage of the heavy chain cross-lin...

The Journal of biological chemistry, Jan 16, 1995

High and low molecular mass kininogen, two multidomain plasma proteins, bind to endothelial cells... more High and low molecular mass kininogen, two multidomain plasma proteins, bind to endothelial cells, platelets, and neutrophils in the intravascular compartment. The specific cell attachment site on their common heavy chain is mediated by domain-3, a cystatin-like structure with inhibitory capacity for papain-like proteinases (Jiang, Y., Müller-Esterl, W., and Schmaier, A. H. (1992) J. Biol. Chem. 267, 3712-3717). In this report, the domain-3 cell binding site is determined by an antibody-directed strategy. The epitope of monoclonal antibody HKH15, which binds to domain-3 and blocks the binding of kininogens to platelets and endothelial cells, was mapped using seven synthetic peptides, which span the entire domain-3 sequence. One peptide, LDC27, specifically bound to HKH15. Fine mapping of the epitope of HKH15 revealed that a minimal 13-residue segment in LDC27, named CNA13, is the antibody binding site. LDC27 and CNA13 inhibited biotinylated high molecular mass kininogen binding to e...

Shock, 2011

Streptococcus pyogenes of the M1 serotype is frequently associated with severe streptococcal infe... more Streptococcus pyogenes of the M1 serotype is frequently associated with severe streptococcal infections. M1 protein challenge can cause widespread microthrombosis, suggesting a role of platelets in streptococcal sepsis. Herein, we hypothesized that platelets may play a role in M1 protein-induced lung inflammation and injury. M1 protein was injected intravenously in C57Bl/6 mice. For platelet and neutrophil depletion, an anti-GP1bα antibody and an anti-Gr-1 antibody, respectively, were administered before M1 protein challenge. Bronchoalveolar fluid and lung tissue were harvested for analysis of neutrophil infiltration, edema, and macrophage inflammatory protein 2 (MIP-2) formation. Blood was collected for analysis of membrane-activated complex 1 (Mac-1) and CD40 ligand (CD40L) expression on neutrophils and platelets as well as soluble CD40L in plasma. M1 protein caused significant pulmonary damage characterized by neutrophil infiltration, increased formation of edema and MIP-2 in the lung, and enhanced Mac-1 expression on neutrophils. However, M1 protein challenge had no effect on platelet surface expression of CD40L or soluble CD40L levels in plasma. Interestingly, platelet depletion had no influence on M1 protein-induced neutrophil recruitment, MIP-2 production, and tissue damage in the lung or Mac-1 expression on neutrophils. Moreover, we observed that M1 protein could bind to neutrophils but not to platelets. On the other hand, neutrophil depletion abolished M1 protein-induced edema formation and tissue damage in the lung. Our data suggest that neutrophils but not platelets are involved in the pathophysiology of M1 protein-provoked pulmonary damage. Thus, neutrophils may constitute a key target in infections caused by S. pyogenes of the M1 serotype.