LPS-induced down-regulation of signal regulatory protein α contributes to innate immune activation in macrophages

Activation of the mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-kappa B) cascades after Toll-like receptor (TLR) stimulation contributes to innate immune responses. Signal regulatory protein ( SIRP) alpha, a member of the SIRP family that is abundantly expressed in macrophages, has been implicated in regulating MAPK and NF-kappa B signaling pathways. In addition, SIRP alpha can negatively regulate the phagocytosis of host cells by macrophages, indicating an inhibitory role of SIRP alpha in innate immunity. We provide evidences that SIRP alpha is an essential endogenous regulator of the innate immune activation upon lipopolysaccharide (LPS) exposure. SIRP alpha expression was promptly reduced in macrophages after LPS stimulation. The decrease in SIRP alpha expression levels was required for initiation of LPS-induced innate immune responses because overexpression of SIRP alpha reduced macrophage responses to LPS. Knockdown of SIRP alpha caused prolonged activation of MAPKs and NF-kappa B pathways and augmented production of proinflammatory cytokines and type I interferon (IFN). Mice transferred with SIRP alpha-depleted macrophages were highly susceptible to endotoxic shock, developing multiple organ failure and exhibiting a remarkable increase in mortality. SIRP alpha may accomplish this mainly through its association and sequestration of the LPS signal transducer SHP-2. Thus, SIRP alpha functions as a biologically important modulator of TLR signaling and innate immunity.