LPS-Induced Down-regulation Of Signal Regulatory Protein A Contributes To Innate Immune Activation In Macrophages

MAPKs and NF-KB cascades after TLR stimulation contributes to innate immune responses. SIRPαis an essential endogenous regulator of the innate immune activation upon LPS exposure. SIRPαexpression was promptly reduced in macrophages after LPS stimulation which was required for initiation of LPS-induced innate immune responses. Knockdown of SIRPa caused prolonged activation of MAPKs and NF-KB pathways and augmented production of proinflammatory cytokines. Mice transferred with SIRPα-depleted macrophages were highly susceptible to endotoxic shock, developing multiple organ failure and exhibiting a remarkable increase in mortality. SIRPa may accomplish this mainly through its association and sequestration SHP-2. Thus, SIRPa functions as a biologically important modulator of TLR signaling and innate immunity.