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

International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai 200438, China

CORRESPONDENCE Hong-Yang Wang: hywangk{at}vip.sina.com

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

Abbreviations used: CHX, cycloheximide; ERK, extracellular signal–related kinase; IKK, IB kinase; IRAK, IL-1 receptor-associated kinase; ISRE, interferon-sensitive response element; JNK, c-Jun NH₂-terminal kinase; MAPK, mitogen-activated protein kinase; MyD88, myeloid differentiation factor 88; NO, nitric oxide; SIRP, signal regulatory protein; sh, short hairpin; SOCS, suppressor of cytokine signaling; TBK1, TANK-binding kinase 1; TLR, Toll-like receptor; Trif, TIR domain-containing adaptor inducing IFN-ß.

X.-N. Kong and H.X. Yan contributed equally to this paper.

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