TLR4 and Sepsis: And extracellular CIRP activity is mediated by TLR4-MD2 complex.72 CIRP treatment increases the ICAM-1+ phenotype of bone marrow derived neutrophils (BMDN) and stimulates the production of iNOS and NETs in a TLR4-dependent manner.136 CIRP stimulates macrophages to release pro-inflammatory cytokines in sepsis and plays an important role in T cell dysregulation.