Intravascular adhesion and recruitment of neutrophils in response to CXCL1 depends on their TRPC6 channels

J Mol Med (Berl). 2020 Mar;98(3):349-360. doi: 10.1007/s00109-020-01872-4. Epub 2020 Jan 16.


Here we report a novel role for TRPC6, a member of the transient receptor potential (TRPC) channel family, in the CXCL1-dependent recruitment of murine neutrophil granulocytes. Representing a central element of the innate immune system, neutrophils are recruited from the blood stream to a site of inflammation. The recruitment process follows a well-defined sequence of events including adhesion to the blood vessel walls, migration, and chemotaxis to reach the inflammatory focus. A common feature of the underlying signaling pathways is the utilization of Ca2+ ions as intracellular second messengers. However, the required Ca2+ influx channels are not yet fully characterized. We used WT and TRPC6-/- neutrophils for in vitro and TRPC6-/- chimeric mice (WT mice with WT or TRPC6-/- bone marrow cells) for in vivo studies. After renal ischemia and reperfusion injury, TRPC6-/- chimeric mice had an attenuated TRPC6-/- neutrophil recruitment and a better outcome as judged from the reduced increase in the plasma creatinine concentration. In the cremaster model CXCL1-induced neutrophil adhesion, arrest and transmigration were also decreased in chimeric mice with TRPC6-/- neutrophils. Using atomic force microscopy and microfluidics, we could attribute the recruitment defect of TRPC6-/- neutrophils to the impact of the channel on adhesion to endothelial cells. Mechanistically, TRPC6-/- neutrophils exhibited lower Ca2+ transients during the initial adhesion leading to diminished Rap1 and β2 integrin activation and thereby reduced ICAM-1 binding. In summary, our study reveals that TRPC6 channels in neutrophils are crucial signaling modules in their recruitment from the blood stream in response to CXCL1. KEY POINT: Neutrophil TRPC6 channels are crucial for CXCL1-triggered activation of integrins during the initial steps of neutrophil recruitment.

Keywords: CXCL1; CXCR2; Neutrophil recruitment; TRPC6 channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cell Adhesion
  • Chemokine CXCL1 / immunology*
  • Chemotaxis
  • Kidney / immunology
  • Kidney / metabolism
  • Kidney Diseases / immunology*
  • Kidney Diseases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / physiology*
  • Reperfusion Injury / immunology*
  • Reperfusion Injury / metabolism
  • TRPC6 Cation Channel / immunology*


  • Chemokine CXCL1
  • Cxcl1 protein, mouse
  • TRPC6 Cation Channel
  • Trpc6 protein, mouse
  • Calcium