Neutrophil mobilization is a crucial response to protect the host against invading microorganisms. Neutrophil recruitment and removal have to be tightly regulated to prevent uncontrolled inflammation and excessive release of their toxic content causing tissue damage and subsequent organ dysfunctions. Neutrophil apoptosis and phagocytosis by resident and recruited macrophages contribute to the safe disposal of engulfed bacteria and toxic metabolites and elicits the production of anti-inflammatory cytokines. Nevertheless, in many organs, macrophage mobilization into the barrier epithelium is dearth and cannot be a major mechanism for homeostasis of inflammation. We suggest that in some mucosal surfaces or barrier epithelium, like urinary and gall bladder or the mammary alveoli, phagocytosis of apoptotic neutrophils by macrophage may not be the only or most important mechanism of neutrophil safe disposal and homeostasis of inflammation. Based on our results we suggest a novel and previously unrecognized mechanism of neutrophil internalization and apoptotic death program in epithelial cells. Viable neutrophils trigger a mechanism that enables them to crawl into cytoplasmic double membrane compartments in the host cells. Thenceforth, internalized neutrophils loose the membrane compartment and undergo apoptotic cell death in the cytoplasm. We were able to demonstrate this incredible phenomena both in vitro on epithelial cell lines and in murine in vivo systems. We hypothesize that this mechanism contributes to safe disposal of neutrophils and for the resolution of inflammation that might have been overlooked, yet is widespread and central mechanism of inflammation control and resolution in some organs and disease processes.
Most significantly we further suggest that some pathogenic bacteria are taking advantage of neutrophil cell invasion process, using it to invade epithelial cells, where they can proliferate. Bacteria invasion to epithelia may be of prime importance in the pathogenesis of major diseases such as bovine mastitis, urinary tract infection (UTI) and typhoid fever and might account for the chronic carriage and relapsing disease caused by mammary pathogenic E. coli (MPEC), urinary pathogenic E. coli (UPEC) and Salmonella enteric subsp. enterica serovar Typhi, respectively.