Sunday, May 18, 2025
5/18/2025
Kindlin-3 signaling in neutrophils - PROJECT SUMMARY/ABSTRACT Inflammation plays a pivotal role in the rapid removal of harmful stimuli, either sterile or infectious; however, uncontrolled inflammation can lead to a variety of chronic inflammatory disorders. Neutrophils constitute the front line of the innate immune response, and swiftly undergo a carefully choreographed process to locate and destroy potentially pathological threats. Neutrophil recruitment is an integrin-dependent, chemotaxis-directed process that is followed by production of reactive oxygen species (ROS) and release of neutrophil extracellular traps (NETs), together which serve to remove or kill the offending agents. To minimize collateral damage to host tissues, however, the killing functions of neutrophils must be carefully regulated in both a temporally and spatially controlled manner; the mechanisms at play to regulate neutrophil activation, however, remain poorly understood. Kindlin-3, an integrin β cytoplasmic domain binding partner, and an essential integrin activator in cells of hematopoietic origin, is known to play an important role in promoting integrin-mediated neutrophil recruitment to the sites of inflammation. Paradoxically, however, we have recently discovered that neutrophil kindlin-3 also acts to suppress ROS production and NET release in an integrin-binding independent manner. Thus, kindlin-3 in neutrophils possesses both pro- and anti-inflammatory properties, indicating that it may function as a bifunctional modulator of neutrophil activation. Interestingly, our preliminary studies have revealed that neutrophil kindlin-3 unexpectedly becomes degraded upon inflammatory challenges. Based on these findings, we propose that degradation of neutrophil kindlin-3 is a key step in the cellular decision tree regulating neutrophil activation under inflammatory conditions. The purpose of this application, therefore, is to explore novel, heretofore unexplored mechanisms regulating kindlin-3 degradation and to examine its functional significance in inflammatory responses. Two Specific Aims are proposed. In Specific Aim 1, we will determine the mechanism by which kindlin-3 undergoes degradation in stimulated neutrophils, including both human and mouse neutrophils. In Specific Aim 2, we will determine the functional significance of kindlin-3 degradation in neutrophils in response to inflammatory challenges, such as under pathological conditions of endotoxemia and acute lung injury. These timely and complementary studies will establish an important and novel role for kindlin-3 in neutrophils in modulating inflammatory responses. Findings made will fill important gaps in our understanding of neutrophil biology, and may lead to novel opportunities for developing more specific and safer anti-inflammatory strategies for treating complications in a whole host of inflammatory diseases, including the recently described inflammatory complications present in COVID-19.
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