Caspase-11 contributes to site-1 protease cleavage and SREBP1 activation in the inflammatory response of macrophages

Front Immunol. 2023 Jan 27:14:1009973. doi: 10.3389/fimmu.2023.1009973. eCollection 2023.

Abstract

Sterol regulatory element-binding proteins (SREBPs) are key transcription factors that control fatty acid and cholesterol metabolism. As the major SREBP isoform in macrophages, SREBP1a is also required for inflammatory and phagocytotic functions. However, it is insufficiently understood how SREBP1a is activated by the innate immune response in macrophages. Here, we show that mouse caspase-11 is a novel inflammatory activator of SREBP1a in macrophages. Upon LPS treatment, caspase-11 was found to promote the processing of site-1 protease (S1P), an enzyme that mediates the cleavage and activation of SREBP1. We also determined that caspase-11 directly associates with S1P and cleaves it at a specific site. Furthermore, deletion of the Casp4 gene, which encodes caspase-11, impaired the activation of S1P and SREBP1 as well as altered the expression of genes regulated by SREBP1 in macrophages. These results demonstrate that the caspase-11/S1P pathway activates SREBP1 in response to LPS, thus regulating subsequent macrophage activation.

Keywords: SREBP (sterol regulatory element-binding protein) pathway; caspase; inflammatory response; macrophage; site-1 protease (S1P).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspases*
  • Lipopolysaccharides
  • Macrophages* / metabolism
  • Mice
  • Sterol Regulatory Element Binding Protein 1* / genetics
  • Sterol Regulatory Element Binding Protein 1* / metabolism

Substances

  • Caspases
  • Lipopolysaccharides
  • membrane-bound transcription factor peptidase, site 1
  • Sterol Regulatory Element Binding Protein 1

Grants and funding

This study was supported by JSPS KAKENHI Grant Numbers JP20H03679, JP20H04956, JP22K19534 (to YO) and JP22K19516 (to IM), JP21H03366 (to SH); AMED Grant Number JP21gm6210023 (to YO); JST Grant Number JPMJMS2023 (to IM); as well as the Takeda Science Foundation and Mitsubishi Foundation (to YO, IM).