MyD88 Promotes Neutrophil Extracellular Trap Formation and Gut Leakiness After Ethanol and Burn Injury

Myeloid differentiation primary-response protein 88 (MyD88), an adapter protein used by many Toll-like receptors (TLRs), plays a critical role in initiating inflammatory responses. Our laboratory has previously shown that alcohol intoxication combined with burn injury causes intestinal tissue damage and leakiness. This is accompanied by increased intestinal neutrophil infiltration along with bacterial abundance and translocation. An overgrowth of bacteria can activate TLRs on intestinal epithelial cells (IECs), promoting inflammation and subsequent gut tissue damage. To examine the role of MyD88 in intestine inflammation/leakiness following ethanol and burn injury, we used MyD88-/- mice. MyD88 deficiency in mice prevented the increases in IL-6 and KC levels, MPO activity, as well as the expression of neutrophil mediators Lipocalin2, S100a8, and S100a9 in the intestine. It also attenuated neutrophil extracellular trap (NET) formation and release of superoxide anion (O2-). In addition, MyD88 deficiency improved tight junction; namely ZO-1, Occludin, Claudin 4 and Claudin 8 expression. Finally, using IEC specific MyD88-/-IEC mice, we further found that MyD88 deficiency mitigated intestinal permeability in ethanol and burn. Together, these findings suggest that MyD88 plays a critical role in intestinal inflammation and barrier leakiness following ethanol and burn injury, and therefore, targeting the MyD88 pathway may have therapeutic potential for intervention in burn injury.