Transient efferocytosis-induced activation of IKKβ reprograms macrophages to promote tissue resolution
) cell expansion. The upstream IKKβ pathway and the downstream resolution pathways are linked through several intermediary molecules, including the transcription factor Myc, the epigenetic modifier ten-eleven translocation-2 (TET2), and the immune checkpoint protein programmed cell death ligand 1 (PD-L1). Deletion of macrophage IKKβ in vivo blocks the above resolution pathways and compromises tissue repair in two efferocytosis-mediated repair settings: resolution of thymic injury after dexamethasone-induced thymocyte apoptosis; and, most importantly, atherosclerosis regression induced by low-density lipoprotein (LDL)-lowering, which is highly relevant to the prevention of cardiovascular disease in humans. These findings illustrate the existence of a unifying upstream signal for efferocytosis-induced resolution, which could suggest new therapeutic strategies to enhance multiple tissue resolution pathways and to optimize anti-inflammatory therapies by avoiding blocking IKKβ-NFκB/p38-mediated resolution.
Authors
- Alan R. Tall (ORCID: https://orcid.org/0000-0002-7708-2417)
- Joshua P. Thaler (ORCID: https://orcid.org/0000-0002-8691-7340)
- Jennifer W. Bradford (ORCID: https://orcid.org/0000-0002-1337-8382)
- Lars Mäegdefessel (ORCID: https://orcid.org/0000-0001-5228-2634)
- David Ngai (ORCID: https://orcid.org/0000-0002-9576-5254)
- Bernhard Dorweiler (ORCID: https://orcid.org/0000-0002-8262-8381)
- Kenneth Walsh (ORCID: https://orcid.org/0000-0001-7580-2276)
- Heather Doviak (ORCID: https://orcid.org/0000-0002-0720-3164)
- Jeremy M. Frey
- Hanna Winter (ORCID: https://orcid.org/0000-0001-8110-8627)
- George Kuriakose
- Mustafa Yalçınkaya (ORCID: https://orcid.org/0000-0003-2199-0886)
- Santosh R. Sukka
- Ira Tabas
- Brian Havens
- Saheli Chowdhury (ORCID: https://orcid.org/0009-0001-2011-1205)
Institutions
- University of Cologne (DE)
- University of Washington (US)
- Augusta University (US)
- Columbia University Irving Medical Center (US)
- TUM Klinikum (DE)
- University Hospital Cologne (DE)
- University of Virginia (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-04-30
- DOI
- https://doi.org/10.64898/2026.04.27.720940
- Primary Topic
- Phagocytosis and Immune Regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00