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
Abstract
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]. "
    [Show abstract] [Hide abstract] ABSTRACT: The cytokines interleukin-11 (IL-11) and IL-6 are important proteins with well-defined pro- and anti-inflammatory functions. They activate intracellular signaling cascades through a homodimer of the ubiquitously expressed signal-transducing β -receptor glycoprotein 130 (gp130). Specificity is gained through the cell- and tissue-specific expression of the nonsignaling IL-11 and IL-6 α -receptors (IL-11R and IL-6R), which determine the responsiveness of the cell to these two cytokines. IL-6 is a rare example, where its soluble receptor (sIL-6R) has agonistic properties, so that the IL-6/sIL-6R complex is able to activate cells that are usually not responsive to IL-6 alone (trans-signaling). Recent evidence suggests that IL-11 can signal via a similar trans-signaling mechanism. In this review, we highlight similarities and differences in the functions of IL-11 and IL-6. We summarize current knowledge about the generation of the sIL-6R and sIL-11R by different proteases and discuss possible roles during inflammatory processes. Finally, we focus on the selective and/or combined inhibition of IL-6 and IL-11 signaling and how this might translate into the clinics.
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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. "
    [Show abstract] [Hide abstract] ABSTRACT: A rapid and robust recruitment of circulating neutrophils at sites of infection is critical for preventing bacterial spread. The efficiency of this process, however, is greatly diminished during sepsis, a severe systemic inflammatory response to infection. The proteolytic activity of a disintegrin and metalloprotease-17 is induced in the cell membrane of leukocytes upon their activation, resulting in the conversion of membrane to soluble TNF-α and the release of assorted receptors from the surface of neutrophils important for their effector functions. We show that conditional knockout mice lacking a disintegrin and metalloprotease-17 in all leukocytes had a survival advantage when subjected to polymicrobial sepsis. Bacteremia and the levels of circulating proinflammatory cytokines, key determinants of sepsis severity, were significantly reduced in conditional a disintegrin and metalloprotease-17 knockout mice during sepsis. Although cecal bacterial microbiota and load were similar in unmanipulated conditional a disintegrin and metalloprotease-17 knockout and control mice, peritoneal spread of bacteria was significantly reduced in conditional a disintegrin and metalloprotease-17 knockout mice following sepsis induction, which was associated with an amplified recruitment of neutrophils. Taken together, our findings suggest that extensive a disintegrin and metalloprotease-17 induction during sepsis may tip the balance between efficient and impaired neutrophil recruitment.
    Article · Apr 2016
    • "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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