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

ABSTRACT: 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 ?2 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.

SUBMITTER: Lindemann O 

PROVIDER: S-EPMC7080674 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature