Helminth Imprinting of Hematopoietic Stem Cells Sustains Anti-Inflammatory Trained Innate Immunity That Attenuates Autoimmune Disease

Abstract

Certain proinflammatory stimuli can metabolically and epigenetically modify monocytes/macrophages or NK cells to be more responsive to secondary stimuli, a process known as trained innate immunity. However, the longevity of trained innate immunity is unclear. In this study, we report that Fasciola hepatica excretory-secretory products (FHES) can imprint an anti-inflammatory phenotype on long-term hematopoietic stem cells (HSCs) and monocyte precursor populations, enhancing their proliferation and differentiation into anti-inflammatory Ly6Clow monocytes. These monocytes expand and populate multiple compartments within mice, conferring hyporesponsiveness to proinflammatory stimuli and reduced susceptibility to induction of experimental autoimmune encephalomyelitis. Mice treated with FHES had enhanced alternatively activated macrophages, reduced Th1 and Th17 responses, and attenuating effects on autoimmunity that persisted for 8 mo. Furthermore, transplantation of HSCs from FHES-treated mice transferred the anti-inflammatory phenotype to naive mice. Our findings demonstrate that helminth products can modulate HSCs to promote development of anti-inflammatory myeloid cells that attenuate T cell–mediated autoimmune disease.

The Effects of Trained Innate Immunity on T Cell Responses; Clinical Implications and Knowledge Gaps for Future Research

“…Trained immunity has been implicated in processes driving ‘inflammageing’ and in age-associated neurodegenerative disease such as Alzheimer’s disease ( 2 , 113 ). Since a skewing of haematopoiesis occurs during trained immunity ( 12 , 25 ), resulting in increased ratios of myelopoiesis to lymphopoieses, it is worthwhile considering how this may affect the T cell repertoire in the long-term. Further work elucidating the kinetics of these skewed ratios over time and what it means for lymphoid cell function will be critical, especially in infants who are forming a T cell repertoire in the thymus from cells that egress from the bone marrow.…”

“…Trained immunity has been implicated in processes driving 'inflammageing' and in age-associated neurodegenerative disease such as Alzheimer's disease (2,113). Since a skewing of haematopoiesis occurs during trained immunity (12,25), resulting in increased ratios of myelopoiesis to lymphopoieses, it is worthwhile considering how this may affect the T cell repertoire in the long-term.…”

“…The majority of studies to date describe trained immunity as enhancing pro-inflammatory responses, however, it was recently reported that myeloid cells can be trained towards an anti-inflammatory phenotype following exposure to helminth products ( 11 , 12 ). Macrophages trained in vitro with Fasciola hepatica total extract (FHTE; Table 1 ) or F. hepatica excretory secretory products (FHES) showed heightened production of the anti-inflammatory cytokines IL-1RA and IL-10, but reduced production of the pro-inflammatory cytokines TNF and IL-12p40 ( 11 ).…”

“…Suppressed IL-12p40 and TNF dampens the Th1 cell response ( 11 , 32 ). FHES administered to mice in vivo altered the hematopoietic stem cell niche in the bone marrow and resulted in hyporesponsive monocytes at different sites in the mice ( 12 ). These data also showed that this anti-inflammatory trained immunity induced by FTHE or FHES was associated with reduced Th1 and Th17 responses and attenuated EAE ( 11 , 12 ), the animal model of autoimmune multiple sclerosis, which is mediated by pathogenic Th1, Th17 and ex-Th17 cells ( 33 ).…”

Trained immunity: A Yin‐Yang balance

“…Sterile tissue injury trained the innate immune system, providing protection against subsequent infection in adult drosophila 75 . The excretory‐secretory products of Fasciola hepatica imprinted a long‐term anti‐inflammatory phenotype in myeloid cells 83 . The induction of trained immunity might also be modulated by circadian rhythm, 76 in a sex‐dependent manner, 77 and by microRNA 78 …”