If dead cells accumulate in the body, they can contribute to inflammation and predispose individuals to multiple chronic inflammatory conditions such as rheumatoid arthritis, cardiovascular diseases, Crohn's disease or lupus by uncharacterized pathways.
The phagocyte NADPH oxidase generates superoxide, the precursor to reactive oxygen species (ROS) that have both antimicrobial and immunoregulatory functions. Inactivating mutations in NADPH oxidase alleles cause chronic granulomatous disease (CGD), characterized by enhanced susceptibility to life-threatening microbial infections and inflammatory disorders, and hypomorphic NADPH oxidase alleles are associated with autoimmunity.
These studies unravel a key role for the NADPH oxidase in the disposal of apoptotic cells by inflammatory macrophages. The oxidants generated promote efferosome maturation and acidification that facilitate the degradation of ingested apoptotic cells.
"Billions of cells die daily as a consequence of regular wear and tear, tissue turnover and during an inflammatory response. The body dedicates a significant amount of energy in the specific recognition and uptake of these dead cells via specific pathways," said Juhi Bagaitkar, Ph.D., a researcher in the University of Louisville School of Dentistry.
"If you don't bury the dead cells, they can burst open and cause harm. However, the underlying mechanisms are incompletely characterized," said Bagaitkar. She along with researchers at Washington University, Indiana University and the University of Michigan, recently published a paper in blood, demonstrating the importance of oxidants in the digestion of apoptotic, or dead cells.
Role of reactive oxygen species
Specifically, the research uncovers how NADPH-oxidase is activated to generate reactive oxygen species (ROS) in macrophages, a kind of white blood cell that eats dead cells. These cells also are involved in getting rid of viruses and bacteria.
The presence of ROS is critical as its generation drives additional mechanisms involved in the digestion of cellular corpses to perform at an optimal level. This allows the macrophage to complete the digestion process of efferocytosis, meaning "to bury the dead."
"Independent of their role in the microbial killing, we are gaining an even greater appreciation of ROS for their huge role in the regulation of host immune response," Bagaitkar said. "Uncovering this role of ROS in the clearance of dead cells sheds some mechanistic insights on how oxidants function in limiting of host inflammation rather than activating it.
"When our bodies produce too much or too little ROS we become pre-disposed to autoimmune disease and chronic inflammation. Producing just enough of the optimal level is what is needed," she said.