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B3 – Immun responses to native and artificial extracellular matrices
Superior goal of this project is to characterize artificial extracellular matrices (aECM) which regulate misbalanced activation of immune cells in chronic wounds and which therefore could be applied as immunomodulating component in dressings for advanced wound therapy.
Classically, chronic wounds are characterized by excessive activity of proteases (MMPs, MPO, neutrophil elastase) and reactive oxygen species (ROS) leading to ulceration of the tissue. This high proteolytic environment arises from an unrestrained inflammatory response maintained by an excess of pro-inflammatory cytokines and uncontrolled invasion of immune cells including granulocytes (PMN), monocytes (MO) and macrophages (MA). Persistent activation of inflammatory M1-MA and compromised phenotype switch towards pro-repair M2-MA hindering inflammatory resolution are particularly critical in this respect. Thus, modulating the activity of immune cells and specifically of MA represents a promising approach in the development of advanced wound therapies.
In our previous investigations we have identified aECM based on sulfated glycosaminoglycans (GAG) exerting direct and indirect immunomodulating effects on immune cells. For example, aECM based on collagen I and artificially sulfated hyaluronan (HA) modulate the pro-inflammatory activity of M1-MA and promote the transition towards pro-repair M2-MA. We showed that this direct immunomodulation is mediated by sulfated HA. It involves the recognition and uptake of sulfated HA via CD44 as well as the scavenging receptors CD36 and LOX-1 and implicates the activation of anti-oxidant proteins. M1-MA treated with sulfated HA show despite their pro-inflammatory activation reduced activity of pro-inflammatory transcription factors resulting in attenuated release of pro-inflammatory cytokines in favour of the production of anti-inflammatory mediators. This anti-inflammatory activity of sulfated HA on M1-MA is independent from its molecular weight and can be regulated by adjusting the degree of sulfation of the HA molecule. Furthermore, we identified an indirect immunomodulating effect of hydrogels composed of star-shaped polyethylenglycol (starPEG) and partially desulfated heparins. Immunomodulation by these hydrogels is based on the binding and functional neutralisation (scavenging) of the chemokines MCP-1 and IL-8 within the hydrogel network that is mediated by the heparin component. Due to this inactivation of pro-inflammatory chemokines the hydrogels indirectly modulate the invasion and activation of PMN, MO und MA.
From these results we are deducing our working hypothesis: Resolution of persistent inflammation and promotion of tissue repair in chronic, non-healing wounds can be achieved by multifunctional GAG-based aECM via direct and indirect immunomodulation. Based on our previous research following aspects are currently addressed in subproject B3:
Analyses of multifunctional and multi-phased starPEG/heparin hydrogels in respect of a multi-step and phase-adapted immunomodulation in chronic wounds
Development and characterization of multifunctional immunomodulating hydrogels based on sulfated HA
Pro-repair effects of the immunomodulating aECM materials will be analysed in mice models of impaired regeneration based on a metabolic syndrome (db/db) or an induced chronic-venous insufficiency (CVI). Mechanisms of immunomodulation will be characterized in complex co-culture systems with human immune cells and human dermal cells as well as in in vivo models of chronic skin inflammation. Finally, identified immunomodulating mechanisms are validated in a translational approach using wound fluids and immune cells from patients with disturbed wound healing due to diabetes mellitus or CVI.
B3 – Immun responses to native and artificial extracellular matrices
Superior goal of this project is to characterize artificial extracellular matrices (aECM) which regulate misbalanced activation of immune cells in chronic wounds and which therefore could be applied as immunomodulating component in dressings for advanced wound therapy.
Classically, chronic wounds are characterized by excessive activity of proteases (MMPs, MPO, neutrophil elastase) and reactive oxygen species (ROS) leading to ulceration of the tissue. This high proteolytic environment arises from an unrestrained inflammatory response maintained by an excess of pro-inflammatory cytokines and uncontrolled invasion of immune cells including granulocytes (PMN), monocytes (MO) and macrophages (MA). Persistent activation of inflammatory M1-MA and compromised phenotype switch towards pro-repair M2-MA hindering inflammatory resolution are particularly critical in this respect. Thus, modulating the activity of immune cells and specifically of MA represents a promising approach in the development of advanced wound therapies.
In our previous investigations we have identified aECM based on sulfated glycosaminoglycans (GAG) exerting direct and indirect immunomodulating effects on immune cells. For example, aECM based on collagen I and artificially sulfated hyaluronan (HA) modulate the pro-inflammatory activity of M1-MA and promote the transition towards pro-repair M2-MA. We showed that this direct immunomodulation is mediated by sulfated HA. It involves the recognition and uptake of sulfated HA via CD44 as well as the scavenging receptors CD36 and LOX-1 and implicates the activation of anti-oxidant proteins. M1-MA treated with sulfated HA show despite their pro-inflammatory activation reduced activity of pro-inflammatory transcription factors resulting in attenuated release of pro-inflammatory cytokines in favour of the production of anti-inflammatory mediators. This anti-inflammatory activity of sulfated HA on M1-MA is independent from its molecular weight and can be regulated by adjusting the degree of sulfation of the HA molecule. Furthermore, we identified an indirect immunomodulating effect of hydrogels composed of star-shaped polyethylenglycol (starPEG) and partially desulfated heparins. Immunomodulation by these hydrogels is based on the binding and functional neutralisation (scavenging) of the chemokines MCP-1 and IL-8 within the hydrogel network that is mediated by the heparin component. Due to this inactivation of pro-inflammatory chemokines the hydrogels indirectly modulate the invasion and activation of PMN, MO und MA.
From these results we are deducing our working hypothesis: Resolution of persistent inflammation and promotion of tissue repair in chronic, non-healing wounds can be achieved by multifunctional GAG-based aECM via direct and indirect immunomodulation. Based on our previous research following aspects are currently addressed in subproject B3:
Analyses of multifunctional and multi-phased starPEG/heparin hydrogels in respect of a multi-step and phase-adapted immunomodulation in chronic wounds
Development and characterization of multifunctional immunomodulating hydrogels based on sulfated HA
Pro-repair effects of the immunomodulating aECM materials will be analysed in mice models of impaired regeneration based on a metabolic syndrome (db/db) or an induced chronic-venous insufficiency (CVI). Mechanisms of immunomodulation will be characterized in complex co-culture systems with human immune cells and human dermal cells as well as in in vivo models of chronic skin inflammation. Finally, identified immunomodulating mechanisms are validated in a translational approach using wound fluids and immune cells from patients with disturbed wound healing due to diabetes mellitus or CVI.
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Signal Transduction and Targeted Therapyno. 1 (2023): 379-3
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Journal of Investigative Dermatologyno. 9 (2023): B31-B31
Theranosticsno. 4 (2022): 1659-1682
Sophia Hauck, Paula Zager,Norbert Halfter, Elke Wandel, Marta Torregrossa,Ainur Kakpenova,Sandra Rother, Michelle Ordieres, Susann Räthel,Albrecht Berg,Stephanie Möller,Matthias Schnabelrauch,
BIOLOGICAL CHEMISTRYno. 11 (2021): 1289-1307
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