Myeloid cells and Epigenetic Plasticity: Mechanisms and Implications in Autoimmune and other Inflammatory Processes

BACKGROUND AND CURRENT STATUS: Myeloid cells are crucial effectors of the innate immune response and essential regulators of adaptive immunity. Myeloid cells are
myeloid cells are extremely plastic in that they respond and terminally differentiate into a diversity of
into a diversity of functional types, in the blood or in tissues, in response to a variety of growth factors.
response to a variety of growth factors, cytokines and pathogenic molecules. This
plasticity is also manifested by the subversion of normal differentiation toward the aberrant generation of alternative
the aberrant generation of alternative varieties of tolerogenic or immunosuppressive myeloid cells in inflammatory
immunosuppressive in inflammatory conditions such as those occurring in autoimmune and autoimmune diseases.
autoimmune and autoinflammatory diseases, in the context of infection and in the tumor microenvironment where
tumor microenvironment where various inflammatory factors are released [Rodríguez-Ubreva et al.
et al., 2017]. The differentiation and activation of myeloid cells requires the fine regulation
fine regulation of gene expression [Alvarez-Errico et al. 2015]. This depends on the interaction of
a variety of elements, including transcription factors and epigenetic mechanisms.
epigenetic mechanisms. Epigenetic mechanisms are largely responsible for the
plasticity of myeloid cells under both physiological and exacerbated inflammatory conditions.
of exacerbated inflammation. The development of compounds that inhibit epigenetic enzymes
epigenetic enzymes provides new therapeutic opportunities for intercepting the connection
between extracellular factors and host myeloid cells [Rodriguez-Ubreva et al.
al., 2017]. In previous projects, our group has determined the connection between diverse
transcriptional factors and epigenetic enzymes that direct methylation changes towards
certain genomic regions both under physiological conditions [de la Rica et al. (2013,
2015) Vento-Tormo et al (2016), Garcia-Gómez et al (2017)] as well as aberrant [Vento-Tormo
et al (2017)]. OBJECTIVES: 1) to identify the mechanistic connection between different stimuli
and the elements that determine the acquisition of specific patterns of epigenetic marks in myeloid cells [Vento-Tormo et al.
epigenetic marks in tolerogenic or immunosuppressive myeloid cells; 2) to identify the
between different stimuli and the acquisition of epigenetic memory in myeloid cells, such as myeloid cells
myeloid cells, such as those of tolerance or trained immunity; 3) determine the methylation profile of myeloid cells, such as those of tolerance or
3) to determine the methylation profile of myeloid cells in three representative rheumatic autoimmune
diseases and to establish their relationship to genetic factors; 4) to determine the methylation profile of myeloid cells in three
4) to determine the methylation profile of myeloid cells in representative autoinflammatory diseases and to
identify the factors involved in the signaling pathways connected with such epigenetic changes.
epigenetic changes.