Much of the biology surrounding macrophage functional specificity has arisen through examining them during inflammation. However, tissue-specific triggers influence macrophage phenotype and function in health. The TAM family of receptor protein tyrosine kinases mediates the non-inflammatory removal of apoptotic cells by phagocytes through the bridging phosphatidylserine-binding molecules Gas6 or Protein S. We show that one such TAM receptor (Axl) is exclusively expressed on mouse airway macrophages, but not interstitial macrophages and other lung leukocytes, under homeostatic conditions and is constitutively ligated to Gas6. Axl expression is potently induced by GM-CSF expressed in the healthy and inflamed airway, and by type I interferon or TLR3 stimulation on human and mouse macrophages, indicating potential involvement of Axl in apoptotic cell removal under inflammatory conditions. Indeed, an absence of Axl does not cause sterile inflammation in health, but leads to exaggerated lung inflammatory disease upon influenza infection. The exacerbation of influenza infection was not due to inability to clear the viruses in Axl-/- mice, but was associated with enhanced weight loss, increased airway cellular infiltrates, and elevated nucleosome release indicative of secondary necrosis. These data imply that Axl allows specific identification of airway macrophages, and that its expression is critical for macrophage functional compartmentalisation in the airspaces or lung interstitium. We propose that this may be a critical feature to prevent excessive inflammation due to secondary necrosis of unefferocytosed apoptotic cells following inflammation.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:721541 |
| Date | January 2014 |
| Creators | Fujimori, Toshifumi |
| Contributors | Hussell, Tracy ; Snelgrove, Robert |
| Publisher | Imperial College London |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/10044/1/49787 |
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