Biology subjects

Schuermans, S.

Publications and source records attributed to Schuermans, S..

4 recordsLinked to original sources

bioRxiv2025

Degradation rather than disassembly of necrotic debris is essential to enhance recovery after acute liver injury

Necrotic cell death causes loss of membrane integrity, release of intracellular contents and deposition of necrotic cell debris. Effective clearance of this debris is crucial for resolving inflammation and promoting tissue recovery. While leukocyte phagocytosis plays a major role, soluble factors in the bloodstream also contribute to debris removal. Our study examined whether enzymatic degradation or disassembly of necrotic debris enhances clearance and improves outcomes in a mouse model of drug-induced liver injury. Using intravital microscopy and proteomic profiling, we demonstrated that necrotic debris is more complex than anticipated, containing DNA, filamentous actin, histones, complement C3, fibrin(ogen) and plasmin(ogen), among many other components. DNase 1 treatment facilitated recovery significantly by enhancing the clearance of DNA from necrotic areas, reducing circulating nucleosomes and actin, and lowering the associated inflammatory response. However, its effect on actin and other damage-associated molecular patterns in necrotic regions was limited. Treatment with short synthetic peptides, specifically 20-amino acid-long positively charged PLK and negatively charged PLE, which displace histones from debris in vitro, did not inhibit liver injury or promote recovery. Moreover, activating plasmin to disrupt fibrin encapsulation via tissue plasminogen activator (tPa) led to increased circulating actin levels and worsening of injury parameters. These findings suggest that fibrin encapsulation is important for containing necrotic debris and that enzymatic degradation of necrotic debris is a more effective strategy to enhance tissue recovery than targeting debris disassembly. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/633891v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@1d324e6org.highwire.dtl.DTLVardef@11b9de7org.highwire.dtl.DTLVardef@1bcc23org.highwire.dtl.DTLVardef@f71a32_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

A central role for CCR2 in monocyte recruitment and blood-brain barrier disruption during Usutu virus encephalitis

Usutu virus (USUV) is an emerging neurotropic flavivirus capable of causing encephalitis in humans. Here, our main goal was to characterize the innate immune response in the brain during USUV encephalitis and to identify strategies to control disease severity. Using an immunocompetent mouse model of USUV encephalitis, we showed that microglia activation, blood-brain barrier (BBB) disruption and inflammatory monocyte recruitment are hallmarks of disease 6 days post infection. Activated microglia were in close association to USUV-infected cells, concomitantly with elevated levels of IL-6, IFN-{gamma}, CCL2, CCL5, CXCL10 and CXCL1 in the brain. Monocyte recruitment was CCR2-dependent and driven by IFN-{gamma} and CCL2 production beneath the brain vasculature. Moreover, CCR2 deficiency inhibited microglia activation and BBB disruption, showing the central role of CCR2 in USUV encephalitis. Accordingly, treatment with dexamethasone prevented pro-inflammatory mediator production and reduced leukocyte recruitment significantly, restraining encephalitis severity. Concluding, USUV encephalitis is driven by CCR2-mediated monocyte recruitment and BBB disruption, and blocked therapeutically by glucocorticoids. SUMMARYThe neurotropic Usutu virus can cause encephalitis driven by CCR2-mediated monocyte recruitment, microglia activation and blood-brain barrier disruption, all of which are inhibited by glucocorticoid treatment.

immunology↗

bioRxiv2024

Complement activation at injury sites drives the phagocytosis of necrotic cell debris and resolution of liver injury

Cells die by necrosis due to excessive chemical or thermal stress, leading to plasma membrane rupture, release of intracellular components and severe inflammation. The clearance of necrotic cell debris is crucial for tissue recovery and injury resolution, however, the underlying mechanisms are still poorly understood, especially in vivo. This study examined the role of complement proteins in promoting clearance of necrotic cell debris by leukocytes and their influence on liver regeneration. We found that independently of the type of necrotic liver injury, either paracetamol (APAP) overdose or thermal injury, complement proteins C1q and (i)C3b were deposited specifically on necrotic lesions via the activation of the classical pathway. Importantly, C3 deficiency led to a significant accumulation of necrotic debris and impairment of liver recovery in mice, which was attributed to decreased phagocytosis of debris by recruited neutrophils in vivo. Monocytes and macrophages also took part in debris clearance, although the necessity of C3 and CD11b was dependent on the specific type of necrotic liver injury. Using human neutrophils, we showed that depletion of C1q or C3 caused a reduction in the volume of necrotic debris that is phagocytosed, indicating that complement promotes effective debris uptake by neutrophils in mice and humans. In summary, complement activation at injury sites is a pivotal event for necrotic debris clearance by phagocytes and determinant for efficient recovery from tissue injury. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/609344v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@14dc246org.highwire.dtl.DTLVardef@d90b1org.highwire.dtl.DTLVardef@9683adorg.highwire.dtl.DTLVardef@19f13c8_HPS_FORMAT_FIGEXP M_FIG C_FIG Key pointsO_LIThe complement cascade is activated on necrotic cell debris in vivo via the classical pathway C_LIO_LIDeficiency in complement C3 impairs necrotic debris clearance and liver recovery after injury C_LIO_LIComplement-mediated debris clearance is performed by neutrophils, monocytes and macrophages C_LIO_LIHuman neutrophils depend on complement opsonization to phagocytose necrotic cell debris efficiently C_LI

immunology↗

bioRxiv2023

Natural antibodies as "eat-me" signals for phagocytosis of necrotic cell debris at sites of tissue injury

Natural antibodies (NAbs) are circulating polyreactive immunoglobulins that bind endogenous and exogenous antigens. Here, we investigated the role of NAbs in driving the clearance of necrotic cell debris from injury sites. Using mouse models of liver injury, we observed that IgM and IgG NAbs opsonize necrotic debris in vivo by recognizing common self-molecules such as histones, actin, phosphoinositides and cardiolipin, but not phosphatidylserine. Importantly, mice lacking NAbs presented impaired recovery from liver injury, which was correlated to sustained presence of necrotic debris in the tissue, prolonged inflammation and reduced hepatocellular proliferation. Mechanistically, necrotic debris phagocytosis was dependent on NAbs in vitro and in vivo, and restitution with total immunoglobulins rescued the defective recovery from liver injury in immunodeficient mice. In summary, we showed that NAbs opsonize necrotic cell debris and act as "eat-me" signals for engulfment through Fc{gamma}Rs and CD11b, driving the recovery from tissue injury. HighlightsO_LINatural antibodies opsonize exposed self-antigens upon necrotic cell death. C_LIO_LIThe phagocytosis of necrotic cell debris requires natural antibodies, Fc{gamma}Rs and CD11b. C_LIO_LINatural antibodies drive cellular proliferation and tissue regeneration after liver injury. C_LIO_LITreatment with natural antibodies improves the recovery from liver injury in both immunodeficient and immunocompetent mice. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/533912v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1ac8a7org.highwire.dtl.DTLVardef@6b7714org.highwire.dtl.DTLVardef@156d7cdorg.highwire.dtl.DTLVardef@720fea_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗