Inhibition of Endogenous Activated Protein C Attenuates Experimental Autoimmune Encephalomyelitis by Inducing Myeloid-Derived Suppressor Cells

Abstract

Activated protein C (APC) is an anti-coagulant involved in the interactions between the coagulation and immune systems. APC has broad anti-inflammatory effects mediated through its ability to modulate leukocyte function and confer vascular barrier protection. We investigated the influence of APC on the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the animal model for multiple sclerosis. We modulated APC levels in the circulation during EAE induction through systemic administration of a monoclonal antibody against protein C/APC (anti-PC). We initially hypothesized that inhibition of APC may result in a heightened inflammatory environment leading to increased EAE pathogenesis. Contrary to this hypothesis, mice treated with anti-PC antibody exhibited attenuated EAE. Interestingly, despite reduced disease severity and minimal pathogenic conditions in the CNS, anti-PC mice exhibited considerable leukocyte infiltration in the brain, comparable to control mice with severe EAE. Furthermore, CD4+ T-cells were diminished in the periphery of anti-PC mice while various CD11b+ populations were increased, notably the myeloid-derived suppressor cells (MDSC), a CD11b+ subset characterized as potent T-cell suppressors. MDSCs from anti-PC mice exhibited increased expression of T-cell-suppressive factors and effectively inhibited T-cell proliferation. Overall, our findings show that APC inhibition affected EAE pathogenesis at multiple fronts; specifically, increasing vascular barrier permeability, as evidenced by considerable leukocyte infiltration in the brain. APC inhibition, additionally, modulated the functional responses of CD11b+ cells leading to the expansion and increased activation of MDSCs, which are suppressive to the CD4+ T-cells required for EAE progression, thereby resulting in attenuated EAE.

Thrombomodulin‐dependent protein C activation is required for mitochondrial function and myelination in the central nervous system

“…Inhibition of endogenous aPC using antibodies surprisingly resulted in protection from EAE , a finding at odds with the current observation and those made by Han et al . and Verbout et al .…”

EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice

“…39,40 Of note, MDSC differentiation is in part regulated by Irf8 41 and may be sensitive to the EPCR ligand aPC. 42 It is currently unknown whether the EPCR-expressing Gr1CD11b POS subset exerts similar, likely stage-and context-specific immunoregulatory functions as MDSC.…”

Phenotypic and functional alterations of myeloid‐derived suppressor cells during the disease course of multiple sclerosis

“…Taken together, the current findings of phenotypic and functional changes of MDSCs, during the MS disease course, indicate a possible role for MDSCs as therapeutic target for prevention of disease progression. The potential therapeutic implication of MDSCs as a target for regulation of autoimmune responses has been explored in some studies using murine models of autoimmune diseases, with encouraging results . However, although manipulation of MDSCs may hold promise as a new therapy in such diseases, it should be noted that interfering with MDSC regulation of immune responses is challenging due to their plasticity and integral role in a variety of T‐cell regulatory pathways.…”