Ongoing research on this topic focuses on an exploration of the unique roles of the eosinophilic leukocyte and its unique secretory mediators in promoting health and restoring homeostasis with an emphasis on antiviral host defense. Our first publication on this report features the alarmin, high mobility group B1 (HMGB1), a mediator that has generated substantial interest with respect to the pathogenesis of eosinophil-associated disorders, including asthmatic inflammation and chronic rhinosinusitis. In this study, our intent was to determine whether HMGB1 could promote eosinophil activation. First, we detected HMGB1 receptors RAGE and toll-like receptor (TLR)4 (but not TLR2) on freshly isolated human eosinophils from healthy donors. However, in contrast to earlier reports which featured supraphysiologic concentrations of HMGB1, we found that physiologic and even relevant pathophysiologic levels of biologically-active HMGB1 had no effect on survival of human eosinophils alone or in combination with pro-survival cytokines IL-5, IL-3, or GM-CSF. Furthermore, these concentrations of HMGB1 had no impact on surface expression of RAGE, TLR2 or TLR4. Similarly, HMGB1 did not elicit chemotaxis of human eosinophils alone and had no effect in combination with the eosinophil chemotactic agent, eotaxin-2 (CCL24). However, surface expression of TLR2 and TLR4 increased in response to cell stress, notably on eosinophils that remain viable after 48 hours without IL-5. As such, our work demonstrates that HMGB1 signaling on eosinophils may be substantially more detailed, and may involve complex immunostimulatory pathways that emerge in vivo that cannot be demonstrated in the more simple, ex vivo systems (Dyer and Rosenberg, 2015, PLoS One 10(3), e0118887) Our second publication features the unique eosinophil-associated ribonuclease, mEar 11, which is a member of an extensive family of divergent proteins of the RNase A family of secretory ribonucleases. As a group, several members of this family maintain independent roles as ribonucleases and modulators of innate immunity. Of interest, mouse Ear 11 is the only RNase A ribonuclease expressed specifically in response to Th2 cytokine stimulation, characteristic of allergic airways disease. In this work, we found that mouse Ear 11 is differentially expressed in tissues other than eosinophils,and that systemic stimulation with IL-33 results in 10-5000-fold increased expression in lung and spleen tissue, respectively. We also found that mouse Ear 11 is enzymatically active, although substantially less so than paralogs mEar 1 and mEar 2. However, in contrast to RNase 2/EDN and mEar 2, which have been characterized as selective chemoattractants for CD11c(+) dendritic cells, mEar 11 has prominent chemoattractant activity instead for F4/80(+)CD11c(-) tissue macrophages. Chemoattractant activity is not dependent on enzymatic activity, and requires no interaction with the pattern recognition receptor, Toll-like receptor 2 (TLR2). Taken together, this work characterizes a divergent eosinophil-associated RNase A ribonuclease with a unique expression pattern and function, and highlights the versatility of this family in promoting innate immunity. (Yamada et al., 2015, Journal of Biological Chemistry 290: 8863-8875.) Related to this topic, I have contributed an invited review focused on the role of the Eosinophil-derived neurotoxin and its mouse orthologs in promoting host defense (2015, IJMS 16, 15442-15455). Likewise, I have contributed an invited book chapter entitled Chapter 03007: Eosinophils to the Encyclopedia of Immunobiology by Elsevier Press (M. Ratcliffe, editor). Finally, we have completed our collaboration with Knopp Biosciences (http://knoppbio.com) in which we contributed to the exploration of Dexpramipexole (KNS-760764) as an agent to combat hypereosinophilia. Under terms of funded CRADA 2013-0713, we examined the potential of this molecule in both tissue culture-based bone marrow-derived eosinophil cultures and the interleukin-5 transgenic hypereosinophilic mouse models.
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