Biology subjects

Willenborg, S.

Publications and source records attributed to Willenborg, S..

4 recordsLinked to original sources

bioRxiv2026

Modes of programmed macrophage cell death govern outcome of cutaneous wound healing

Misregulation of tissue repair programs can severely compromise repair outcome. Timely clearance of inflammatory macrophages through regulated cell death is a prerequisite for resolution of inflammation and successful repair. How different modes of macrophage regulated cell death regulate repair and direct healing outcome remains unclear. Using inducible genetic models to trigger macrophage necroptosis (FADDiMKO) or enhance apoptosis of macrophages (cIAP1iMKOcIAP2-/-), we reveal opposing effects on the architecture of the wound tissue. Macrophage necroptosis profoundly disrupted tissue organization: FADDiMKO wounds exhibited reduced numbers of reparative (IL-4RLy6Clow) macrophages, delayed inflammatory resolution, accompanied by a hemorrhagic granulation tissue and reduced myofibroblast differentiation in the mid-phase of repair. In striking contrast, increased apoptosis preserved fundamental tissue architecture and vascular integrity, and reduced scar formation. Furthermore, single-cell transcriptomics demonstrated that macrophage necroptosis disrupts tissue-wide cellular communication networks essential for coordinated repair, in particular macrophage-fibroblast crosstalk. These findings establish that wound healing quality depends on both mode and rate of macrophage programmed death, providing a framework for therapeutic targeting of macrophages in wound healing disorders and fibrotic diseases.

immunology↗

bioRxiv2023

FADD- and RIPK3-mediated cell death ensures timely clearance of wound macrophages and promotes wound healing

Cells of the monocyte/macrophage lineage are an integral component of the bodys innate ability to restore tissue function after injury. In parallel to mounting an inflammatory response, clearance of monocytes/macrophages from the wound site is critical to re-establish tissue functionality and integrity during the course of healing. The role of regulated cell death in macrophage clearance from damaged tissue and its implications for the outcome of the healing response is little understood. Here, we explored the role of macrophage-specific FADD-mediated cell death on Ripk3-/- background in a mechanical skin injury model in mice. We found that combined inhibition of RIPK3-mediated necroptosis and FADD-caspase-8-mediated apoptosis in macrophages profoundly delayed wound healing. Importantly, RIPK3 deficiency alone did not considerably alter the wound healing process and macrophage population dynamics, arguing that inhibition of FADD-caspase-8-dependent death of macrophages is primarily responsible for the delayed wound closure. Notably, TNF blockade reversed the accumulation of Ly6Chigh macrophages induced by combined deficiency of FADD and RIPK3, indicating a critical dual role of TNF-mediated pro-survival and cell death signalling, particularly in this highly pro-inflammatory macrophage subset. Our findings reveal a previously uncharacterized cross-talk of inflammatory and cell death signalling in macrophages in regulating repair processes in the skin.

immunology↗

bioRxiv2022

Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair

Cell death coordinates repair programs following pathogen attack and tissue injury. However, aberrant cell death can interfere with such programs and cause organ failure. cFLIP is a crucial regulator of cell death and a substrate of Caspase-8. Yet, the physiological role of cFLIP cleavage by Caspase-8 remains elusive. Here, we discovered an essential role for cFLIP cleavage in restraining cell death in different pathophysiological scenarios. Mice expressing a cleavage-resistant cFLIP mutant, CflipD377A, exhibited increased sensitivity to SARS-CoV-induced lethality, impaired skin wound healing and increased tissue damage caused by Sharpin deficiency. In vitro, abrogation of cFLIP cleavage sensitizes cells to TNF-induced necroptosis and apoptosis by favoring complex-II formation. Mechanistically, the cell death-sensitizing effect of the D377A mutation depends on Gln(Q)469. These results reveal a crucial role for cFLIP cleavage in controlling the amplitude of cell death responses occurring upon tissue stress, to ensure the execution of repair programs.

cell biology↗

bioRxiv2021

Predictive framework of macrophage activation

Macrophages populate every organ during homeostasis and disease, displaying features of tissue imprinting and heterogeneous activation. The disjointed picture of macrophage biology that emerged from these observations are a barrier for integration across models or with in vitro macrophage activation paradigms. We set out to contextualize macrophage heterogeneity across mouse tissues and inflammatory conditions, specifically aiming to define a common framework of macrophage activation. We built a predictive model with which we mapped the activation of macrophages across 12 tissues and 25 biological conditions, finding a striking commonality and finite number of transcriptional profiles, which we modelled as defined stages along four conserved activation paths. We verified this model with adoptive cell transfer experiments and identified transient RELM[a] expression as a feature of macrophage tissue engraftment. We propose that this integrative approach of macrophage classification allows the establishment of a common predictive framework of macrophage activation in inflammation and homeostasis. One Sentence SummaryWe propose an integrative approach of macrophage classification that allows the establishment of a common framework of macrophage activation in inflammation and homeostasis.

immunology↗