Using primary peritoneal macrophages and specific agonists and antagonists, we reveal the mechanism(s) of action that enable balanced agonists of this pair of nuclear receptors, PPARα/γ, to reverse some of the fundamental imbalances of the innate immune system in IBD, such that immunity can be achieved without overzealous inflammation (Fig. 1; Step 2). The gene discussed is PPARA; the disease is inflammatory bowel disease.