Description:
<jats:title>Abstract</jats:title>
<jats:p>Excessive activation of innate immune cells drives many diverse inflammatory human diseases, such as septic shock and autoimmunity. Many modern therapies employ immunosuppressants and other tolerogenic agents (TAs) to treat inflammation through inhibiting inflammatory cytokines and other effector molecules secreted from innate immune cells. TAs carry side effects due to general immunosuppression and off-target effects. One alternative is TA combination therapy, which could reduce side-effects through dose sparing and may improve therapeutic efficacy. To this end, multiple commonly used TAs were screened for synergistic inhibition of inflammation. Screened TAs included immunosuppressants and steroids used in the clinical treatment of allergy, arthritis, and autoimmune disease, as well as candidate drugs in preclinical testing. Anti-inflammatory potential was determined by inhibition of reactive oxygen species from activated macrophages in culture. Synergistic inhibition was calculated mathematically for TAs combined in various ratios. At least 4 synergistic hits were obtained from the screen, with minimum combination indices ranging from 0.5 (good synergy) to 0.04 (extreme synergy). All other tested TAs showed additive improvement in combination. Each synergistic combination included dexamethasone (DXM). Using DXM in combination with an otherwise ineffective TA may have reduced serum levels of inflammatory cytokines in a mouse model of septic shock. We conclude that using DXM in combination with other TAs may improve the inhibition of macrophage inflammation in multiple clinical applications.</jats:p>