Eosinophil networking under the microscope

Hall and colleagues (page 2014) have succeeded in applying a protein transduction approach to analyze the role of the ras/ERK pathway in primary human eosinophils. This pathway has been studied before in eosinophils with often equivocal results. In this report Hall and colleagues have managed to transduce eosinophils with a dominant-negative N17 H-Ras protein at very high efficiency. This has allowed the authors to examine the outcome of several signaling pathways and biologic activities of eosinophils stimulated with IL-5. The results are quite compelling in that the ras/ERK pathway appears to be selectively affected. Furthermore, the survival effect of IL-5 on eosinophils is severely compromised, allowing the authors to offer a strong, direct link between signaling and function.

Primary cells and, in particular, short-lived cells such as eosinophils are notoriously difficult to transduce in a way that maintains their morphologic and functional integrity. The fact that this can now be achieved offers the potential of inhibiting discrete steps in the eosinophil signaling machinery to analyze functional outcomes. The possibility therefore arises of establishing a cause-and-effect link between signaling pathways and function. This work should also encourage more work on primary eosinophils and less emphasis on transduced cell lines, which often do not offer the same range of functions or exhibit their own signaling machinery, which makes extrapolation to the eosinophil rather risky. Given the role of not only eosinophils but also myeloid cells in general in serious inflammatory conditions such as asthma, there is the further potential of clinically applying the protein transduction approach to selectively inhibit myeloid cell function in vivo. Clearly reducing myeloid cell survival would offer significant benefits in asthma. The proof of principle has been established. The challenge remains of how best to apply this approach to dissect signaling pathways and ultimately to translate these findings into the clinical setting.