The response of macrophages to infectious microorganisms is enhanced by interferon (IFN) g through gene expression modulation, which results in an increased ability to respond to infection, phagocytose and present antigen. We have shown that the local production of IFNg in the heart, mediated by iNKT cells, protects mice during infection with Borrelia burgdorferi (Bb), the causative agent of Lyme disease. Our preliminary data also show that a mechanism that mediates the action of IFNg in macrophages is through the repression of expression of methylation-controlled J protein (MCJ), a member of the DnaJ protein family of cochaperones. MCJ loss of expression has been implicated in the resistance of cancer cells to chemotherapeutic drugs. However, its physiological function, especially in innate immune cells is unknown. Our preliminary data show for the first time, that MCJ is a negative regulator of macrophage responses to Bb. MCJ modulates TLR-mediated responses, and regulates the surface expression of the antigen-presenting molecule CD1d. Our central hypothesis is that the cochaperone MCJ negatively regulates the expression of CD1d by macrophages and the production of IFNg by iNKT cells that infiltrate the infected heart, affecting the regulatory loop of macrophage activation. As a corollary, we propose that IFNg protects against Lyme carditis by repressing the expression of MCJ in macrophages. To test this hypothesis we intend to (aim 1) assess the modulation of Lyme carditis and the local immune response, including iNKT cell activation, in mice that lack MCJ;as well as the specific contribution of macrophage MCJ;
and (aim 2) address the regulation of macrophage responses by MCJ, including their capacity to present antigens to iNKT cells, through the control of the level of proteins that mediate these responses. These studies will provide evidence of the contribution of the IFNg target, MCJ to the response of macrophages to infectious agents and the identification of potential targets of therapeutic intervention.
Our long-term goals are to define the mechanisms by which the cytokine IFN? augments macrophage responses to the causative agent of Lyme disease, Borrelia burgdorferi and modulates cardiac inflammation. We propose that IFN? protects against Lyme carditis through the negative regulation of the newly described cochaperone family member, MCJ. Our studies will focus on the role of MCJ in the response of macrophages to B. burgdorferi in vitro and in vivo, including their phagocytic activity and their antigen presenting capacity to iNKT cells.
| Navasa, Nicolás; Martín, Itziar; Iglesias-Pedraz, Juan Manuel et al. (2015) Regulation of oxidative stress by methylation-controlled J protein controls macrophage responses to inflammatory insults. J Infect Dis 211:135-45 |
| Navasa, Nicolás; Martin-Ruiz, Itziar; Atondo, Estíbaliz et al. (2015) Ikaros mediates the DNA methylation-independent silencing of MCJ/DNAJC15 gene expression in macrophages. Sci Rep 5:14692 |
| Hatle, Ketki M; Gummadidala, Phani; Navasa, Nicolás et al. (2013) MCJ/DnaJC15, an endogenous mitochondrial repressor of the respiratory chain that controls metabolic alterations. Mol Cell Biol 33:2302-14 |
