Abscisic acid (ABA) has shown efficacy in the treatment of diabetes and
inflammation; however, its molecular targets and the mechanisms of action underlying its immunomodulatory effects remain unclear. This study investigates the role of
peroxisome proliferator-activated receptor γ (
PPAR γ) and
lanthionine synthetase C-like 2 (LANCL2) as molecular targets for ABA. We demonstrate that ABA increases
PPAR γ reporter activity in RAW 264.7 macrophages and increases
ppar γ expression in vivo, although it does not bind to the
ligand-binding domain of
PPAR γ. LANCL2 knockdown studies provide evidence that ABA-mediated activation of macrophage
PPAR γ is dependent on lancl2 expression. Consistent with the association of LANCL2 with
G proteins, we provide evidence that ABA increases cAMP accumulation in immune cells. ABA suppresses LPS-induced
prostaglandin E(2) and MCP-1 production via a
PPAR γ-dependent mechanism possibly involving activation of
PPAR γ and suppression of NF-κB and nuclear factor of activated T cells. LPS challenge studies in
PPAR γ-expressing and immune cell-specific
PPAR γ null mice demonstrate that ABA down-regulates
toll-like receptor 4 expression in macrophages and T cells in vivo through a
PPAR γ-dependent mechanism. Global transcriptomic profiling and confirmatory quantitative RT-PCR suggest novel candidate targets and demonstrate that ABA treatment mitigates the effect of LPS on the expression of genes involved in
inflammation, metabolism, and cell signaling, in part, through
PPAR γ. In conclusion, ABA decreases LPS-mediated
inflammation and regulates innate immune responses through a bifurcating pathway involving LANCL2 and an alternative,
ligand-binding domain-independent mechanism of
PPAR γ activation.