Tim4 recognizes carbon nanotubes and mediates phagocytosis leading to granuloma formation

Cell Rep. 2021 Feb 9;34(6):108734. doi: 10.1016/j.celrep.2021.108734.


Macrophage recognition and phagocytosis of crystals is critical for the associated fibrosis and cancer. Of note, multi-walled carbon nanotubes (MWCNTs), the highly representative products of nanotechnology, induce macrophage NLRP3 inflammasome activation and cause asbestosis-like pathogenesis. However, it remains largely unknown how macrophages efficiently recognize MWCNTs on their cell surfaces. Here, we identify by a targeted screening of phagocyte receptors the phosphatidylserine receptors T cell immunoglobulin mucin 4 (Tim4) and Tim1 as the pattern-recognition receptors for carbon crystals. Docking simulation studies reveal spatiotemporally stable interfaces between aromatic residues in the extracellular IgV domain of Tim4 and one-dimensional carbon crystals. Further, CRISPR-Cas9-mediated deletion of Tim4 and Tim1 reveals that Tim4, but not Tim1, critically contributes to the recognition of MWCNTs by peritoneal macrophages and to granuloma development in a mouse model of direct mesothelium exposure to MWCNTs. These results suggest that Tim4 recognizes MWCNTs through aromatic interactions and mediates phagocytosis leading to granulomas.

Keywords: Caspase-1; IL-1β; Tim-1; Tim-4; molecular dynamics simulation; nanomaterials.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Granuloma / genetics
  • Granuloma / metabolism*
  • Humans
  • Macrophages, Peritoneal / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • NIH 3T3 Cells
  • Nanotubes, Carbon*
  • Phagocytosis*
  • THP-1 Cells


  • Membrane Proteins
  • Nanotubes, Carbon
  • TIM-4 protein, mouse
  • TIMD4 protein, human