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. We previously showed 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 after ethanol and burn injury, we used MyD88-/- mice. MyD88 deficiency in mice prevented the increases in interleukin-6 and keratinocyte-derived chemokine levels, myeloperoxidase activity, as well as the expression of neutrophil mediators Lipocalin2, S100a8, and S100a9 in the intestine. It also attenuated neutrophil extracellular trap formation and release of superoxide anion. In addition, MyD88 deficiency improved tight junction protein expression, namely that of ZO-1, OCLN, CLDN4, and CLDN8. Finally, using IEC-knockout MyD88-/- mice, we further found that MyD88 deficiency mitigated intestinal permeability after ethanol and burn injury. Together, these findings suggest MyD88 plays a critical role in intestinal inflammation and barrier leakiness after ethanol and burn injury. Therefore, targeting the MyD88 pathway may have therapeutic potential for intervention in burn injury.