Non-canonical caspase-8 activation by cathepsin B drives anti-inflammatory human macrophage polarization
Year: 2026
Type: article
Abstract: Anti-inflammatory monocyte-derived macrophages are essential to maintain tissue homeostasis but can also contribute to disease progression, notably in cancer and fibrosis. Deciphering the signaling pathways that govern their generation could therefore unlock new therapeutic opportunities. Here we uncover a previously unrecognized, non-apoptotic function of caspase-8 in driving both monocyte-to-macrophage differentiation and anti-inflammatory macrophages polarization. We identified cathepsin B as a novel upstream activator of caspase-8 through a non-canonical cleavage mechanism, conferring to caspase-8 an original activity profile distinct from its apoptotic role. Disruption of this cathepsin B-caspase-8 axis, either genetically or pharmacologically, not only impairs the generation of anti-inflammatory macrophages but also reprograms them towards a pro-inflammatory phenotype. Our findings position the cathepsin B-caspase-8 axis as an original critical regulatory node in macrophage fate decisions and a promising target for therapeutic reprogramming of human macrophages in cancer, inflammation and fibrotic diseases.
Source: Cell Death and Differentiation
Authors: Emeline Kerreneur, Chloé Delaby, Morgane Fajolles, Maxence Bourgoin, Paul Chaintreuil, Sonia Boulakirba, Amaury Aouad, Cécile Favreau, Adèle Rivault, Juba Bennour, Nathalie Droin, Jean-François Peyron, Johanna Chiche, Els Verhoeyen, Anne Doye, Laurent Boyer, Alexandre Gallerand, Stoyan Ivanov, Thomas Cluzeau, Michaël Loschi, Patrick Auberger, Guillaume Robert, Arnaud Jacquel
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,790
OpenAlex ID: W4417290520