lipid-mediated Control of immune system life and death
(and all the steps in between)
S1P signaling in response to genotoxic stress
Despite the risk of long-term damage to bone marrow stem cells by cancer radiotherapy and the increasing threat of radiation exposure as a weapon of terror, there are no safe and effective FDA-approved therapies for protection from ionizing radiation. The Blaho Lab is investigating how blocking or amplifying radiation-induced S1P signaling pathways may affect hematopoietic stem cells and the endothelial cells that share the bone marrow niche. Several FDA-approved drugs targeting this pathway already exist (fingolimod/Gilenya, ozanimod/Zeposia, siponimod/Mayzent, ponesimod/Ponvory), which make it likely that this project will have immediate and far-reaching impact on cancer patients receiving radiotherapy and our ability to protect military and civilian personnel from radiation sickness or side-effects.
How does myeloid cell S1P receptor expression affect their development and ability to modulate the adaptive immune system?
Innate immune (myeloid) cells are the immune system's first responders. Their recruitment and activation is critical for generating effective immunity. Although appreciated for their roles in active immune responses, the contribution of myeloid cells to the homeostatic maintenance of lymphocyte populations is not as well characterized. The Blaho Lab is utilizing mouse strains that have myeloid cell-specific inducible knockout or over-expression of S1P receptors to examine how myeloid-intrinsic S1P receptor signals modulate communication between the innate and adaptive immune systems. Using models of multiple sclerosis (EAE) and immunization, we’re finding that signals transduced via myeloid S1P receptors may fundamentally alter how myeloid cells instruct adaptive immune responses when confronted with pathogens or stimulatory self-antigens.
ApoM-S1P regulation of immune cell proliferation and development
Activation and mobilization of lymphocytes is a tightly controlled process, the dysregulation of which can have severe pathophysiological consequences. Although the majority (~65%) of plasma S1P is bound to apolipoprotein M (ApoM) in the high-density lipoprotein (HDL) particle, how the ApoM-S1P complex regulates immunity is mostly uncharacterized. While dispensable for trafficking, ApoM-S1P restrains lymphopoiesis by activating the receptor S1P1 on bone marrow lymphocyte progenitors. Apom-/- mice have more lymphocyte progenitors in the bone marrow and develop more severe EAE. It’s long been known that HDL can affect lymphocyte proliferation and maturation, but whether ApoM-S1P plays a role is unknown. The Blaho Lab is investigating how the ApoM-S1P-S1P receptor signaling axis may regulate the lymphocyte compartment at various stages of ontogeny, from progenitor to mature cell, by differentially affecting proliferation or phenotype. Thus, S1P chaperones may provide developmental stage-specific novel targets for the modulation of adaptive immunity.