Abstract
SummaryNeutrophils are key components of the innate immune response, providing host defence against infection and being recruited to non‐microbial injury sites. Platelets act as a trigger for neutrophil extravasation to inflammatory sites but mechanisms and tissue‐specific aspects of these interactions are currently unclear. Here, we use bacterial endotoxin in mice to trigger an innate inflammatory response in different tissues and measure neutrophil invasion with or without platelet reduction. We show that platelets are essential for neutrophil infiltration to the brain, peritoneum and skin. Neutrophil numbers do not rise above basal levels in the peritoneum and skin and are decreased (~60%) in the brain when platelet numbers are reduced. In contrast neutrophil infiltration in the lung is unaffected by platelet reduction, up‐regulation of CXCL‐1 (2·4‐fold) and CCL5 (1·4‐fold) acting as a compensatory mechanism in platelet‐reduced mice during lung inflammation. In brain inflammation targeting platelet receptor GPIbα results in a significant decrease (44%) in platelet‐mediated neutrophil invasion, while maintaining platelet numbers in the circulation. These results suggest that therapeutic blockade of platelet GPIbα could limit the harmful effects of excessive inflammation while minimizing haemorrhagic complications of platelet reduction in the brain. The data also demonstrate the ability to target damaging brain inflammation in stroke and related disorders without compromising lung immunity and hence risk of pneumonia, a major complication post stroke. In summary, our data reveal an important role for platelets in neutrophil infiltration to various tissues, including the brain, and so implicate platelets as a key, targetable component of cerebrovascular inflammatory disease or injury.
Highlights
The innate immune response provides rapid defence against infection, injury or disease
We assessed the contribution of platelets to neutrophil-mediated inflammation across a variety of tissue beds, to investigate tissue-specific mechanisms of innate immunity, as we have previously shown in the context of interleukin-1 (IL-1) [9]
Platelets are essential for neutrophil invasion to the peritoneum, skin and brain, but not lung after LPS-induced inflammation Until recently, the precise mechanism of platelet-neutrophil interaction in vivo during innate immune responses was unclear
Summary
The innate immune response provides rapid defence against infection, injury or disease. We have shown that mechanisms of neutrophil invasion following an innate immune challenge can be unique to their target tissue, allowing for tissue specific anti-inflammatory interventions [9]. This may be especially important when targeting components of the immune system that are susceptible to infections, such as after stroke and spinal cord injury [10,11]. We assessed the contribution of platelets to neutrophil-mediated inflammation across a variety of tissue beds, to investigate tissue-specific mechanisms of innate immunity, as we have previously shown in the context of interleukin-1 (IL-1) [9]. We investigated whether plateletdependent neutrophil infiltration could be blocked, without reducing platelet numbers and increasing the risk of haemorrhage after cerebral inflammation
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