BRP39 Regulates Neutrophil Recruitment in NLRP3 Inflammasome-Induced Liver Inflammation

Cell Mol Gastroenterol Hepatol. 2024;17(3):481-497. doi: 10.1016/j.jcmgh.2023.12.002. Epub 2023 Dec 12.

Abstract

Background & aims: Breast regression protein 39 (BRP39) (Chi3L1) and its human homolog YKL-40, is an established biomarker of liver fibrosis in nonalcoholic steatohepatitis (NASH) patients, but its role in NASH pathogenesis remains unclear. We recently identified Chi3L1 as one of the top up-regulated genes in mice with inducible gain-of-function NOD-like receptor protein 3 (NLRP3) activation that mimics several liver features of NASH. This study aimed to investigate the effects of BRP39 deficiency on NLRP3-induced liver inflammation using tamoxifen-inducible Nlrp3 knockin mice sufficient (Nlrp3A350V CRT) and deficient for BRP39 (Nlrp3A350V/BRP-/- CRT).

Methods: Using Nlrp3A350V CRT mice and Nlrp3A350V BRP-/- CRT, we investigated the consequences of BRP39 deficiency influencing NLRP3-induced liver inflammation.

Results: Our results showed that BRP39 deficiency in NLRP3-induced inflammation improved body weight and liver weight. Moreover, liver inflammation, fibrosis, and hepatic stellate cell activation were reduced significantly, corresponding to significantly decreased Ly6C+ infiltrating macrophages, CD68+ osteopontin-positive hepatic lipid-associated macrophages, and activated Lymphocyte antigen 6 complex locus G6D positive (Ly6G+) and citrullinated histone H3 postivie (H3Cit+) neutrophil accumulation in the liver. Further investigation showed that circulatory neutrophils from NLRP3-induced BRP39-deficient mice have impaired chemotaxis and migration ability, and this was confirmed by RNA bulk sequencing showing reduced immune activation, migration, and signaling responses in neutrophils.

Conclusions: These data showcase the importance of BRP39 in regulating the NLRP3 inflammasome during liver inflammation and fibrotic NASH by altering cellular activation, recruitment, and infiltration during disease progression, and revealing BRP39 to be a potential therapeutic target for future treatment of inflammatory NASH and its associated diseases.

Keywords: Fibrosis; LAMs; LY6G; NASH.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fibrosis
  • Hepatitis*
  • Humans
  • Inflammasomes / metabolism
  • Inflammation / metabolism
  • Mice
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Proteins
  • Neutrophil Infiltration
  • Non-alcoholic Fatty Liver Disease* / pathology

Substances

  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLR Proteins
  • Chil1 protein, mouse