Odd couple: The unexpected partnership of glucocorticoid hormones and cysteinyl-leukotrienes in the extrinsic regulation of murine bone-marrow eosinopoiesis

Abstract

Granulopoiesis in murine bone-marrow is regulated by both intrinsic and extrinsic factors (including hormones, drugs, inflammatory mediators and cytokines). Eosinophils, a minor subpopulation of circulating leukocytes, which remains better understood in its contributions to tissue injury in allergic disease than in its presumably beneficial actions in host defense, provide a striking example of joint regulation of granulopoiesis within murine bone-marrow by all of these classes of extrinsic factors. We first described the upregulation of eosinopoiesis in bone-marrow of allergen-sensitized mice following airway allergen challenge. Over the last decade, we were able to show a critical role for endogenous glucocorticoid hormones and cytokines in mediating this phenomenon through modification of cytokine effects, thereby supporting a positive association between stress hormones and allergic reactions. We have further shown that cysteinyl-leukotrienes (CysLT), a major proinflammatory class of lipid mediators, generated through the 5-lipoxygenase pathway, upregulate bone-marrow eosinopoiesis in vivo and in vitro. CysLT mediate the positive effects of drugs (indomethacin and aspirin) and of proallergic cytokines (eotaxin/CCL11 and interleukin-13) on in vitro eosinopoiesis. While these actions of endogenous GC and CysLT might seem unrelated and even antagonistic, we demonstrated a critical partnership of these mediators in vivo, shedding light on mechanisms linking stress to allergy: GC are required for CysLT-mediated upregulation of bone-marrow eosinopoiesis in vivo, but also attenuate subsequent ex vivo responses to CysLT. GC and CysLT therefore work together to induce eosinophilia, but through subtle regulatory mechanisms also limit the magnitude of subsequent bone-marrow responses to allergen.

Keywords: Bone marrow, Leukotriene, Eosinophil, Stress, Glucocorticoid

Core tip: The bone-marrow is exquisitely sensitive to regulation by systemic events, which selectively increase production of different blood cell types to meet transient increases in demand following injury. An association between stress and allergy has long been known, but its mechanisms remain incompletely understood. The exploration of underlying mechanisms in a variety of murine models yielded evidence of separate but interrelated roles for adrenal glucocorticoid hormones and cysteinyl-leukotrienes in coupling systemic events to bone-marrow responses in vivo. We here discuss how these unlikely partners work together to promote eosinophilia but through subtle mechanisms also limit its magnitude.