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

Kindlin-3 negatively regulates the release of neutrophil extracellular traps.
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Xu Z, Ni B, Cao Z, Zielonka J, Gao J, Chen F, Kalyanaraman B, White GC, Ma YQ,


Xu Z, Ni B, Cao Z, Zielonka J, Gao J, Chen F, Kalyanaraman B, White GC, Ma YQ, (click to view)

Xu Z, Ni B, Cao Z, Zielonka J, Gao J, Chen F, Kalyanaraman B, White GC, Ma YQ,

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Journal of leukocyte biology 2018 04 14() doi 10.1002/JLB.3AB0118-005R
Abstract

Neutrophils fight infections by generating reactive oxygen species (ROS) and extracellular traps (NETs). However, how neutrophils modulate ROS/NET 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 ROS/NET generation in neutrophils. When overexpressing kindlin-3 in neutrophil-like differentiated HL-60 cells (HL-60N), ROS/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 ROS/NET generation, suggesting that the role of kindlin-3 in inhibiting ROS/NET signaling may be independent of its binding to integrins. Consistently, knockdown of kindlin-3 in HL-60N cells led to enhanced ROS/NET generation. In addition, bone marrow neutrophils isolated from kindlin-3-deficient mice showed elevated ROS/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 ROS/NET signaling, providing a novel mechanism for fine-tuning neutrophil behaviors during inflammation.

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