Matrix protein Tenascin-C expands and reversibly blocks maturation of eosinophil progenitors

Abstract

Abstract While eosinophil depletion is a sought after strategy in treating allergic disease, little is known about the local tissue factors regulating eosinophils. In disease, eosinophils encounter provisional extracellular matrix (ECM) glycoproteins such as Tenascin-C (TNC), which strongly correlates with eosinophil expansion in tissues. While restricted in healthy adult lungs, TNC is a hematopoietic niche component in bone marrow stroma and is expressed de novo during wound healing or in pathologic epithelial remodeling in asthma. RNA-Seq shows that exposing naïve murine eosinophils to TNC upregulates immaturity markers (CD34, CD117, and Sca-1) and suppresses IL-5Rα. Thus, we hypothesized that TNC represents a factor in the provisional allergic tissue microenvironment that could support in situ eosinophil progenitor expansion. In murine bone marrow-derived cultures, TNC: 1) 3-fold expanded the available Lin−Sca1+ early precursor pool; 2) downregulated IL-5Rα expression on Lin− CD45+ c-kit+ cells during the eosinophil lineage commitment phase; 3) served as a reversible eosinophil maturation block, as TNC withdrawal rescued maturation and increased final eosinophil yield. Moreover, TNC knockout mice lack in situ lung expansion of Lin− c-kit+ CD34+ common myeloid progenitors and Lin− Siglec-F+ Sca-1+ cells in an allergic inflammation model as well as exhibit accelerated lung eosinophil maturation ex vivo. Adding TNC to lung homogenates cultured in IL-5 ex vivo suppressed eosinophil maturation in a manner consistent with TNC block of eosinophil maturation in bone marrow-derived cultures. Together, our results stress the local tissue factor potential to promote in situ expansion and eosinophil persistence in allergic disease.