Serum amyloid A overrides Treg anergy via monocyte-dependent and Treg-intrinsic, SOCS3-associated pathways

The acute phase protein serum amyloid A (SAA) has been well characterized as an indicator of inflammation. Nevertheless, its functions in pro versus anti-inflammatory processes remain obscure. Here we provide unexpected evidences that SAA induces the proliferation of the tolerogenic subset of regulatory T cells (Treg). Intriguingly, SAA reverses Treg anergy via its interaction with monocytes to activate distinct mitogenic pathways in Treg but not effector T cells. This selective responsiveness of Treg correlates with their diminished expression of SOCS3 and is antagonized by Treg–specific induction of this regulator of cytokine signaling. Collectively, these evidences suggest a novel anti-inflammatory role of SAA in the induction of a micro-environment that supports Treg expansion at sites of infection or tissue injury, likely to curb (auto)-inflammatory responses.