Thymic Stromal Lymphopoietin-Mediated Extramedullary Hematopoiesis Promotes Allergic Inflammation

Abstract

SUMMARY Extramedullary hematopoiesis (EMH) refers to the differentiation of hematopoietic stem cells (HSCs) into effector cells that occurs in compartments outside of the bone marrow. Previous studies linked pattern recognition receptor (PRR)-expressing HSCs, EMH and immune responses to microbial stimuli. However, whether EMH operates in broader immune contexts remains unknown. Here, we demonstrate a previously unrecognized role for thymic stromal lymphopoietin (TSLP) in promoting the population expansion of progenitor cells in the periphery and identify that TSLP-elicited progenitors differentiated into effector cells including macrophages, dendritic cells and granulocytes; and that these cells contributed to type 2 cytokine responses. The frequency of circulating progenitor cells was also increased in allergic patients with a gain-of-function polymorphism in TSLP, suggesting the TSLP-EMH pathway may operate in human disease. These data identify that TSLP-induced EMH contributes to the development of allergic inflammation and indicate that EMH is a conserved mechanism of innate immunity.

Metronidazole—but not IL-10 or prednisolone—rescues Trichuris muris infected C57BL/6 IL-10 deficient mice from severe disease

“…It can occur for a variety of reasons but in this instance we expect that tissue inflammation, injury, and repair; and abnormal sys- temic or local chemokine production is the most likely cause. In a mouse model of T. muris infection, Siracusa and colleagues recently demonstrated a splenic extramedullary population of hematopoietic progenitor cells that is responsive to thymic stromal lymphopoietin (TSLP) during the subsequent Type 2 allergic response (Siracusa et al, 2013). Adoptive transfer of these granulocyte monocyte progenitors demonstrated that they influenced germinal center hyperplasia, elevated serum IgE, and accelerated worm expulsion from the gut.…”

Genome-wide association studies in asthma: progress and pitfalls

“…The TSLP association with eosinophilic esophagitis 53 is another condition highly dependent on T H 2 cells and cytokines. 55,56 Inhibition of TSLP activity by intravenous injection of a human anti-TSLP antibody for up to 3 months attenuated both early and late bronchial reactions to exposure to allergen challenge, supporting the role of this protein in allergic asthma and highlighting its potential as a therapeutic target. 57 The MHC locus has been associated with asthma and asthma-related phenotypes in many studies, and its role in the development and activation of T cells makes HLA alleles key regulators of immunopathology.…”

Mast Cells, Basophils and Mucosal Immunity

“…In addition, mouse basophil precursors isolated from mouse bone marrow express the two chains of the TSLP receptor and can develop into basophils under the influence of TSLP. Administration of TSLP to mice also elicits the development of a distinct population of granulocyte-monocyte progenitor cells that can develop into basophils under the influence of IL-3 or TSLP (Siracusa et al, 2013). Basophils developed under the influence of TSLP have different characteristics than IL-3-induced basophils ( Table 2) .…”