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Papers of the Week

2020 Mar

J Mol Med (Berl)



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


Lindemann O, Rossaint J, Najder K, Schimmelpfennig S, Hofschröer V, Wälte M, Fels B, Oberleithner H, Zarbock A, Schwab A
J Mol Med (Berl). 2020 Mar; 98(3):349-360.
PMID: 31950205.


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 Ca ions as intracellular second messengers. However, the required Ca 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 Ca transients during the initial adhesion leading to diminished Rap1 and β 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.