Bone and blood: IL-19 to the rescue

In this issue of Blood, Xiao et al¹  identified interleukin 19 (IL-19) as a potent cytokine capable of promoting expansion and proliferation of neutrophils. Neutropenia is a common consequence of chemotherapy, and there are currently very few and limited treatments available. Surprisingly, osteocytes, the bone cells deeply embedded in the mineralized matrix, are the major source of IL-19, placing these cells, once again, on the list of important regulators of hematopoiesis.^2,3  Osteocytes primary function is to control skeletal homeostasis through 2 secreted proteins: sclerostin,^4,5  a Wnt inhibitor that suppresses bone formation, and Rankl, a cytokine required for osteoclastogenesis.⁶  In this article, Xiao et al used a combination of genetically modified mice and in vitro models to provide evidence that osteocytes are also the main source of IL-19, a cytokine that promotes the expansion of neutrophils.

The article presents 2 major advancements in the field: the identification of IL-19 as a regulator of neutrophils maturation and proliferation and that the osteocytes (and possibly late mature osteoblasts) are the major source of this cytokine.

IL-19 functions as an anti-inflammatory and proangiogenic factor.⁷  It belongs to a subfamily that includes IL-20, IL-22, IL-14, and IL-26, and it signals by binding to a receptor complex consisting of an heterodimer of IL-20Rα and IL-20Rβ promoting a T helper 2 regulatory T-cell⁸  response in a variety of disease contexts.

In this article, the authors first analyzed the role of mechanistic target of rapamycin complex 1 (mTORC1) in osteocytes by generating mice where the expression of this protein was increased, by deleting its inhibitor, tuberous sclerosis complex protein 1 (TSC1), or decreased, by deleting the upstream activator Rheb. mTORC1 regulates both cell proliferation in response to metabolic challenges and myeloid differentiation.⁹  When mTORC1 is activated in Dmp1-expressing cells, neutrophils are significantly increased, whereas mTORC1 inhibition induces neutropenia. The in vivo studies are followed by an extensive in vitro characterization of the relative contribution of different cell types, including osteocytes, osteoclasts, endothelial cells, bone marrow stromal cells, lymphocytes, and monocytes. Strikingly, only primary osteocytes recapitulate the in vivo phenotype. Next, the authors identify IL-19 as the factor driving the hematopoietic phenotype. As predicted, IL-19 administration rescues the neutropenia present in the Dmp1-TSC1 knockout (KO) mice, whereas intramedullary administration of IL-19–neutralizing antibody corrects the neutrophilia in the Dmp1-Rheb KO animals. Last, and possibly most importantly, administration of IL-19 protects wild-type mice from neutropenia induced by both chemotherapy and radiation, demonstrating the therapeutic efficacy of this cytokines. It remains unknown whether IL-19 has additional effects on other organs or tissues, but its potential application in neutropenic states is undoubted. Additional studies will be needed to determine whether factors known to control osteocytes also regulate IL-19 synthesis and secretion and whether this cytokine has additional skeletal and other organ effects. Tissue distribution and downstream signals have only been partially elucidated, and a clearer picture of the function of this cytokine is required. One puzzling finding of this paper is that the phenotype is present only in Dmp1-TSC1 KO animals, and not in mice in which Tsc1 is ablated in osteoprogenitors (Osx-TSC1 KO) or osteoblasts (Ocn-TSC1 KO). This suggests that Tsc1 expression in these cells (osteoprogenitors and osteoblasts) prevents the expansion of neutrophils present in Dmp1-Tsc1 KO animals. One possible explanation is that when Tsc1 is ablated from early osteoprogenitors and osteoblasts, the hematopoietic stem cell niche is altered and can no longer support the expansion of guanosine monophosphate. Further characterization of the hematopoietic phenotype of Osx and Oc-Tsc1 mice will be needed to try to explain this conundrum.

Regardless of these questions, this study is a breakthrough in the development of novel therapeutic interventions to treat neutropenic states.