Investigation of type 2 cytokine pathways as modulators of haematopoiesis during chronic inflammation

Thesis

Chronic inflammatory diseases often promote bone marrow (BM) myelopoiesis at the expense of erythropoiesis and lymphopoiesis, facilitating production of mature myeloid cells to sustain the inflammatory response. In previous studies, type 2 cytokines, including IL-4, IL-5, and IL-33, have been suggested as possible regulators of haematopoiesis, but their role in modulation of haematopoiesis during inflammation was unknown. Spondyloarthritis (SpA) is a chronic inflammatory disease of people that has systemic sequelae, including anaemia. Although associated with type 17 immune responses, there is evidence of a concurrent type 2 response in the intestine of people with SpA. In this thesis, I sought to bring these areas of investigation together by asking if a possible type 2 immune module in murine SpA might be implicated in changes in haematopoiesis, and whether this would be important for progression of disease.

I find inflammation perturbs haematopoiesis in murine SpA, causing a marked bias towards myelopoiesis in the BM, as well as accumulation of myeloid progenitors in spleen and inflamed joints. Conversely, BM erythropoiesis is suppressed, resulting in anaemia. I find that mice also have evidence of a type 2 immune module in the intestine, with increased numbers of cells producing IL-4 and IL-5, and increased production of IL-33. Of these cytokines, IL-4 has pro-myelopoietic effects in vivo and ex vivo, but my results suggest this pathway is not important for development of clinical disease or expansion of myelopoiesis in SpA. Conversely, I find that IL-33 specifically suppresses differentiation of erythroid progenitors. This effect is implicated in development of anaemia in SpA, with IL-33 also causing resistance to the effects of erythropoietin (EPO). Interleukin-33 also promotes myelopoiesis through a combination of direct and indirect effects on progenitor stages, indicating that IL-33 has co-ordinated effects in different parts of the haematopoietic system that may be consistent with its role as an alarmin.

Collectively, my work reveals IL-4 and IL-33 as regulators of myelopoiesis, which may be important in disease settings associated with increased production of these cytokines. I further identify IL-33 as a mediator of anaemia of inflammatory disease and EPO resistance in murine SpA, suggesting that IL-33 could be a therapeutic target for this prevalent and debilitating comorbidity in people with chronic inflammation.

Authors: Swann, JW

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Anaemia; Haematopoiesis; Spondyloarthritis; Erythropoiesis; Immunology; Inflammation; Haematology
• Subjects: Anaemia; Immunology; Inflammation; Haematology