Serum amyloid A induces mitogenic signals in regulatory T cells via monocyte activation

•SAA induces IL-1β and IL-6 secretion from monocytes.•IL-1β and IL-6 are required for the expansion of Treg by SAA.•IL-1β and IL-6 activate ERK1/2 and AKT signaling in Treg in response to SAA.•SAA induces monocyte maturation toward tolerogenic HLA-DRhiHVEMlo dendritic cell.

Serum amyloid A (SAA) has recently been identified by our group as a mitogen for regulatory T cells (Treg). However, the molecular mechanism by which SAA induces Treg proliferation is unknown. Here we provide evidence that IL-1β and IL-6 are directly involved in the SAA-mediated proliferation of Treg. By engaging its several cognate receptors, SAA induces IL-1β and IL-6 secretion by monocytes and drives them toward an HLA-DRhi HVEMlo phenotype resembling immature dendritic cells, which have been implicated in tolerance generation. This monocyte-derived cytokine milieu is required for Treg expansion, as inhibition of IL-1β and IL-6 abrogate the ability of SAA to induce Treg proliferation. Furthermore, both IL-1β and IL-6 are required for ERK1/2 and AKT signaling in proliferating Treg. Collectively, these results point to a novel mechanism, by which SAA initiates a monocyte-dependent process that drives mitogenic signals in Treg.