Therefore, we bred a global Tlr4-/- deficiency state into Townes-AA mice expressing normal human adult hemoglobin A and Townes-SS mice expressing sickle hemoglobin S. We demonstrate that loss of TLR4 in SCD does not alter chronic hemolysis, but does decrease response to an acute stimulus with hemin, LPS or ischemia through loss of downstream NF-κB signaling. This evidence concerns the gene NFKB1 and Schnyder corneal dystrophy.