NLRP3 inflammasome constrains liver regeneration through impairing MerTK-mediated macrophage efferocytosis.

Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE

Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]-

Liver Regeneration* ; NLR Family, Pyrin Domain-Containing 3 Protein*/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein*/genetics ; c-Mer Tyrosine Kinase*/metabolism ; c-Mer Tyrosine Kinase*/genetics ; Macrophages*/metabolism ; Inflammasomes*/metabolism ; Hepatectomy* ; Mice, Knockout*; Animals ; Mice ; Phagocytosis ; Humans ; Indenes/pharmacology ; Sulfones/pharmacology ; Male ; Mice, Inbred C57BL ; Sulfonamides/pharmacology ; Liver/metabolism ; Hepatocytes/metabolism ; Disease Models, Animal ; Efferocytosis ; Furans

The NOD-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in human acute and chronic liver diseases. However, the role and cell-specific contribution of NLRP3 in liver regeneration remains unclear. Here, we found that NLRP3 was highly activated during the early stage of liver regeneration via 70% partial hepatectomy (PHx) mice model and clinical data. Global NLRP3 depletion or pharmacologically blocking NLRP3 significantly enhanced liver regeneration, while NLRP3 overexpression impaired it after PHx. Furthermore, mice with myeloid-specific knockout of Nlrp3 ( Nlrp3 ^{Δ mye} ), rather than hepatocyte-specific knockout ( Nlrp3 ^{Δ hep} ), showed improved liver regeneration compared to control ( Nlrp3 ^fl/fl ). Mechanistically, deficiency of Nlrp3 promoted myeloid-epithelial-reproductive tyrosine kinase (MerTK)-mediated efferocytosis, thereby inducing macrophages toward a pro-reparative Ly6C ^lo phenotype. Notably, NLRP3 inhibition by MCC950 effectively reversed the impairment of liver regeneration after PHx in mice fed a high-fat diet. Our findings provide a potential therapeutic strategy for the prevention and treatment of post-hepatectomy liver failure.

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0 (NLR Family, Pyrin Domain-Containing 3 Protein)
EC 2.7.10.1 (c-Mer Tyrosine Kinase)
0 (Inflammasomes)
0 (Nlrp3 protein, mouse)
EC 2.7.10.1 (Mertk protein, mouse)
6RS86E2BWQ (N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide)
0 (Indenes)
0 (Sulfones)
0 (Sulfonamides)
0 (Furans)

Date Created: 20250101 Date Completed: 20250101 Latest Revision: 20250104

20250104

PMC11691640

10.1126/sciadv.adq5786

39742469