The Journal of immunology : official journal of the American Association of Immunologists
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Robust lung inflammation is one of the prominent features in the pathogenesis of acute lung injury (ALI). Macrophage migration and recruitment are often seen at the early stage of lung inflammatory responses to noxious stimuli. Using an acid inhalation-induced lung injury model, we explored the mechanisms by which acid exposure initiates macrophage recruitment and migration during development of ALI. ⋯ Mechanistically, acid-induced epithelial MV miR-17/221 promoted β1 integrin recycling and presentation back onto the surface of macrophages, in part via a Rab11-mediated pathway. Integrin β1 is known to play an essential role in regulating macrophage migration. Taken together, acid-induced ALI results in epithelial MV shuttling of miR-17/221 that in turn modulates macrophage β1 integrin recycling, promoting macrophage recruitment and ultimately contributing to lung inflammation.
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Despite decades of clinical and biomedical research, the pathogenesis of sepsis and its spectrum of diseases (severe sepsis and septic shock), which are leading causes of death in intensive care units, are still poorly understood. In this article, we show that signaling via the p110δ isoform of PI3K is critical for survival in experimental sepsis. Mice with an inactive knock-in mutation in the p110δ gene (p110δD910A) succumbed acutely to nonlethal dose LPS challenge. ⋯ We confirmed the clinical relevance of these findings by showing that human Tregs also regulate neutrophil function and survival. Collectively, our results show that PI3K δ is essential for survival during sepsis. In addition, our data highlight the importance of Tregs in regulating the pathogenesis of sepsis and septic shock via their effects on neutrophil survival and function, and provide evidence of regulation of innate immunity by cells of the adaptive immune system.