Schematic representation of how microbial products (LPS, MDP) are detected by TLR4 and NOD2. TLR4 and NOD2 are the best studied innate immune receptors present during GVHD. For clarity, the pathways have been simplified. NOD2 sense intracellular MDP, leading to recruitment of the adaptor protein RiCK as well as to activation of the caspase 1 inflammasome, which eventually results in cell death. Extracellular LPS is recognized by TLR4, which signals through its intracellular domain TIR. Subsequent steps involve the adaptor molecules MyD88, TiRAP, TRAM, and TRiF. The activation and translocation of nuclear factor κB (NF-κB) and IRF-3 result in the transcriptional up-regulation of proinflammatory genes. Whether the CARD domain interacts with caspase is controversial as indicated by a dotted line. TIR indicates Toll–IL-1 receptor, the cytoplasmic domain of TLR4; TRAM, Toll–IL-1R domain–containing adaptor inducing interferon-β–related adaptor molecule; TRiF, TIR domain–containing adapter-inducing interferon-β; MyD88, myeloid differentiation primary response gene; TiRAP, Toll–IL-1 receptor (TIR) domain–containing adaptor protein; and IRF-3, interferon regulatory factor 3.