Kindlin-3 negatively regulates the release of neutrophil extracellular traps.

Neutrophils fight infections by generating reactive oxygen species and extracellular traps (NETs). However, how neutrophils modulate generation is mechanistically unclear. Kindlin-3, an essential integrin activator expressed in hematopoietic cells, is required to support integrin-mediated neutrophil recruitment during inflammation. Here, we report a novel role of kindlin-3 in regulating duanyu1670/NET generation in neutrophils. When overexpressing kindlin-3 in neutrophil-like differentiated HL-60 cells (HL-60N), duanyu1670/NET generation from these cells were significantly suppressed. Interestingly, overexpression of a kindlin-3 mutant that is defective for interacting with integrins in HL-60N cells still inhibited duanyu1670/NET generation, suggesting that the role of kindlin-3 in inhibiting duanyu1670/NET signaling may be independent of its binding to integrins. Consistently, knockdown of kindlin-3 in HL-60N cells led to enhanced duanyu1670/NET generation. In addition, bone marrow neutrophils isolated from kindlin-3-deficient mice showed elevated duanyu1670/NET generation when compared with WT counterparts. As expected, overexpression of exogenous kindlin-3 in mouse neutrophils could suppress NET release ex vivo and in vivo. Collectively, these results demonstrate that kindlin-3 in neutrophils is involved in modulating the duanyu1670/NET signaling, providing a novel mechanism for fine-tuning neutrophil behaviors during inflammation.

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