IRAK-M is a negative regulator of Toll-like receptor (TLR) signaling. TLRs detect microorganisms and activate immune responses by signaling through MyD88 and the serine/threonine kinase IRAK. The IRAK family includes two active kinases, IRAK and IRAK-4, and two inactive kinases, IRAK-2 and IRAK-M. IRAK-M is expressed in monocytes/macrophages and negatively regulates TLR signaling by preventing the dissociation of IRAK and IRAK-4 from MyD88 and the formation of IRAK-TRAF6 complexes. IRAK-M knockout mice show increased cytokine production and inflammatory responses to bacterial infection, and have impaired endotoxin tolerance. IRAK-M is induced by TLR stimulation and is required for endotoxin tolerance, indicating its role in innate immune homeostasis. IRAK-M inhibits TLR signaling by preventing IRAK and IRAK-4 dissociation from the TLR signaling complex. IRAK-M also inhibits the release of IRAK-4 from MyD88. IRAK-M is a key component of the feedback regulatory system of innate immunity, playing a critical role in maintaining immune homeostasis. The study shows that IRAK-M is a negative regulator of TLR signaling and is essential for endotoxin tolerance. IRAK-M is induced by TLR stimulation and is required for endotoxin tolerance, indicating that IRAK-M is a key component of a feedback regulatory system of innate immunity. IRAK-M plays a critical role in the maintenance of homeostasis of the innate immune system.IRAK-M is a negative regulator of Toll-like receptor (TLR) signaling. TLRs detect microorganisms and activate immune responses by signaling through MyD88 and the serine/threonine kinase IRAK. The IRAK family includes two active kinases, IRAK and IRAK-4, and two inactive kinases, IRAK-2 and IRAK-M. IRAK-M is expressed in monocytes/macrophages and negatively regulates TLR signaling by preventing the dissociation of IRAK and IRAK-4 from MyD88 and the formation of IRAK-TRAF6 complexes. IRAK-M knockout mice show increased cytokine production and inflammatory responses to bacterial infection, and have impaired endotoxin tolerance. IRAK-M is induced by TLR stimulation and is required for endotoxin tolerance, indicating its role in innate immune homeostasis. IRAK-M inhibits TLR signaling by preventing IRAK and IRAK-4 dissociation from the TLR signaling complex. IRAK-M also inhibits the release of IRAK-4 from MyD88. IRAK-M is a key component of the feedback regulatory system of innate immunity, playing a critical role in maintaining immune homeostasis. The study shows that IRAK-M is a negative regulator of TLR signaling and is essential for endotoxin tolerance. IRAK-M is induced by TLR stimulation and is required for endotoxin tolerance, indicating that IRAK-M is a key component of a feedback regulatory system of innate immunity. IRAK-M plays a critical role in the maintenance of homeostasis of the innate immune system.