Helminth products promote anti-inflammatory trained innate immunity by imprinting long-term hematopoietic stem cells
Citation:
Cunningham, Kyle, Helminth products promote anti-inflammatory trained innate immunity by imprinting long-term hematopoietic stem cells, Trinity College Dublin.School of Biochemistry & Immunology, 2021Download Item:
Completed Thesis_Kyle Cunningham.pdf (PDF) 7.119Mb
Abstract:
Recent research has shown that immunological memory is not confined to the cells of the adaptive immune system but can be imbued upon innate immune cells, including monocytes and macrophages, in a process known as trained innate immunity. While the exact mechanisms remain largely uncharacterized, it is thought to require epigenetic and metabolic reprogramming induced by pathogens that modify the innate immune cell to respond faster and more robustly to secondary challenge. Recently, our laboratory has demonstrated that mature macrophages can undergo anti-inflammatory trained innate immunity following in vitro and in vivo exposure to helminth-derived products. Macrophages trained with helminth products secreted more anti-inflammatory but less pro-inflammatory cytokines, which resulted in modulated T cell responses that mediated the autoimmune disease experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. However, macrophages and monocytes are often short-lived cells, and this has led to uncertainty over the longevity of trained innate immunity in mature innate immune cells found in the periphery. There is emerging evidence to suggest that hematopoietic stem cells (HSCs) in the bone marrow (BM) can be modified to produce mature innate immune cells with enhanced pro-inflammatory effector functions in a process now known as central trained innate immunity.
This study demonstrated that excretory-secretory products of the helminth Fasciola hepatica (FHES) can imprint an anti-inflammatory phenotype on long-term HSCs (LT-HSCs) and monocyte precursor populations, enhancing their proliferation and differentiation into anti-inflammatory Ly6Clow monocytes. These monocytes expand and populate multiple compartments in mice, conferring hyporesponsiveness to pro-inflammatory stimuli and reduced susceptibility to induction of EAE. Furthermore, treatment of mice with FHES enhanced myelopoiesis, and reduced inflammatory innate immune responses and suppressed migration of pathogenic Th1 and Th17 cells into the central nervous system (CNS) during EAE.
Anti-inflammatory modifications to the BM persisted for up to 8 months. Furthermore, transplantation of whole BM from mice treated with FHES transferred a bias for myelopoiesis and promoted the generation of anti-inflammatory macrophages in recipient mice that reduced susceptibility to the induction of EAE. Moreover, FACS-sorted LT-HSCs from mice treated with FHES were also capable of transplanting anti-inflammatory central trained innate immunity to recipient mice. Inhibition of epigenetic or metabolic reprogramming during FHES stimulation of BM cells blocked the development of anti-inflammatory central training in vitro.
The findings demonstrate that helminth-derived products can epigenetically and metabolically reprogram HSCs to promote development of anti-inflammatory myeloid cells in response to secondary challenge, resulting in suppressed pathogenic T cells that mediate EAE. The demonstration that helminths and their products can induce long-lasting modifications to BM-resident HSCs to produce anti-inflammatory innate immune cells sheds new light on innate immune memory and has the potential to identify novel therapeutic approaches for autoimmune diseases.
Author's Homepage:
https://tcdlocalportal.tcd.ie/pls/EnterApex/f?p=800:71:0::::P71_USERNAME:CUNNINKYDescription:
APPROVED
Author: Cunningham, Kyle
Advisor:
Mills, KingstonPublisher:
Trinity College Dublin. School of Biochemistry & Immunology. Discipline of BiochemistryType of material:
ThesisAvailability:
Full text availableKeywords:
Helminths, Trained innate immunity, Hematopoietic stem cells, HSC, HematopoiesisLicences: