NIH Research Festival
Autoimmune and inflammatory diseases are characterized by pathologic levels of immune activation. One therapeutic strategy involves generating immunosuppressive macrophage that will down-regulate these over-exuberant immune responses. While immunosuppressive macrophage can be induced by a cocktail of cytokines including M-CSF, IL-4 and IL-10, such an approach is poorly suited to the treatment of chronic diseases. As an alternative, we explored the ability of Pam3CSK4 (PAM3), an agonist of the Toll-like receptor 2/1 heterodimer, to stimulate human monocytes to differentiate into immunosuppressive macrophage. We find that PAM3-generated macrophage express CD163, CD206, PD-L2, DC-SIGN and SR-A (established markers of suppressive macrophage) and secrete anti-inflammatory cytokines including IL-10 and IL-1Ra. Functionally, macrophage generated from PAM3 treated monocytes are strongly endocytic and suppress the proliferation of autologous CD4+ T cells. Microarray analysis coupled with inhibition studies demonstrate that PAM3-driven monocyte differentiation involves the activation of NF-KB, Akt, Erk and p38 MAPK signaling pathways. Whereas NF-KB and Akt mediate the general process of monocyte-to-macrophage differentiation, blockade of Erk or p38 MAPK selectively interferes with the generation of immunosuppressive (rather than inflammatory) macrophage. The therapeutic potential of PAM3 was evaluated by studying monocytes from patients with dermatomyositis. While other TLR agonists stimulated these monocytes to produce pro-inflammatory cytokines such as IL-12 and TNFa, PAM3 induced them to differentiate into immunosuppressive macrophage. Studies in Rhesus macaques verified that PAM3 promoted the generation of immunosuppressive macrophage in vivo and triggered their production of anti-inflammatory mediators (IL-10 and IDO) with no toxicity. These findings show that PAM3 promotes the polarization of primate monocytes into immunosuppressive macrophage via a p38 MAPK/Erk pathway that could be useful in the treatment of inflammatory and autoimmune conditions.
Scientific Focus Area: Immunology
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