Leukocyte ADAM17 Regulates Acute Pulmonary Inflammation

Article (PDF Available)inPLoS ONE 6(5):e19938 · May 2011with18 Reads
DOI: 10.1371/journal.pone.0019938 · Source: PubMed
The transmembrane protease ADAM17 regulates the release and density of various leukocyte cell surface proteins that modulate inflammation, including L-selectin, TNF-α, and IL-6R. At this time, its in vivo substrates and role in pulmonary inflammation have not been directly examined. Using conditional ADAM17 knock-out mice, we investigated leukocyte ADAM17 in acute lung inflammation. Alveolar TNF-α levels were significantly reduced (>95%) in ADAM17-null mice following LPS administration, as was the shedding of L-selectin, a neutrophil-expressed adhesion molecule. Alveolar IL-6R levels, however, were reduced by only ≈25% in ADAM17-null mice, indicating that ADAM17 is not its primary sheddase in our model. Neutrophil infiltration into the alveolar compartment is a key event in the pathophysiology of acute airway inflammation. Following LPS inhalation, alveolar neutrophil levels and lung inflammation in ADAM17-null mice were overall reduced when compared to control mice. Interestingly, however, neutrophil recruitment to the alveolar compartment occurred earlier in ADAM17-null mice after exposure to LPS. This decrease in alveolar neutrophil recruitment in ADAM17-null mice was accompanied by significantly diminished alveolar levels of the neutrophil-tropic chemokines CXCL1 and CXCL5. Altogether, our study suggests that leukocyte ADAM17 promotes inflammation in the lung, and thus this sheddase may be a potential target in the design of pharmacologic therapies for acute lung injury.
    • "However , in contrast to other substrates like CD62L, shedding of the IL-6R by ADAM17 on T cells appears to be rather weak [77, 83]. In a murine model of LPS-induced acute pulmonary inflammation, mice with a genetic deletion of ADAM17 in leukocytes displayed only 25% reduction of sIL-6R levels in alveolar fluid, suggesting that ADAM17 is not the primary sheddase of the IL-6R [84] . In contrast, the increase in sIL- 6R levels one hour after intravenous LPS injection, a model of endotoxemia, was clearly dependent on ADAM17 [83]. "
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    • "In unmanipulated , conditional ADAM17 knockout and control mice, peritoneal neutrophil counts were very low and did not differ significantly (6125 6 5303 and 7587 6 1749, respectively; means 6 SD, n = 3 mice in each group). Neutrophil absolute and differential counts in the blood of these mice were equivalent as well (data not shown), as reported previously [26][27][28] . Conditional ADAM17 knockout mice, however, exhibited significantly higher levels of peritoneal neutrophils at all time points examined post-CLP (Fig. 4C), revealing that the targeting of ADAM17 in leukocytes increases neutrophil recruitment during sepsis. "
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    • "only in CAST/EiJ mice (data not shown). It was reported for various inflammation models that in mice deficient in E-, L-, or P-selectin genes (Sele, Sell, Selp), the levels of neutrophils , T lymphocytes and lung inflammation are reduced6869707172. All selectin genes were similarly up-regulated in all three susceptible genes in the lung after infection. "
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