Adenosine Signaling via the A1 Receptor Reverses Age-Related Decline in Neutrophil Function
Neutrophils are an important component of the innate immune system, mounting a first response to infectious pathogens. An insufficient neutrophil response leads to a far more serious infection. Researchers here report on an exploration of mechanisms responsible for rousing neutrophils to action, and how they change with age. They find that stimulation of a specific cell surface receptor can reverse the age-related decline in efficiency of the neutrophil response to at least one specific infectious pathogen. Thus this might prove to be the basis for therapies capable of improving the capacity of the aged immune system to protect against infectious disease.
Despite the availability of vaccines and antibiotics, Streptococcus pneumoniae remain the leading cause of community-acquired pneumonia in the elderly. Immunosenescence, the overall decline in immunity that occurs with age, contributes to the increased susceptibility of the elderly to infection. We and others previously found that neutrophils (polymorphonuclear leukocytes or PMNs) are required for host defense against S. pneumoniae infections as they are needed for initial control of bacterial numbers upon infection.
Extracellular adenosine (EAD) is key for host resistance to pneumococcal infection. Upon tissue injury triggered by a variety of insults, including infection, ATP is released from cells and metabolized to adenosine. EAD is recognized by four G protein-coupled receptors, A1, A2A, A2B, and A3. These receptors are ubiquitously expressed on many cell types including PMNs and can have opposing effects on immune responses.
Aging is accompanied by changes in EAD production and signaling. However, the role of the EAD pathway in immunosenescence remains practically unexplored. We previously found that triggering A1 receptor signaling in old mice significantly enhanced their resistance to pneumococcal lung infection and reduced the ability of S. pneumoniae to bind pulmonary epithelial cells. The objective of this study was to explore the age-driven changes in the EAD pathway and its impact on PMN function.
PMNs from old mice failed to efficiently kill pneumococci ex vivo; however, supplementation with adenosine rescued this defect. To identify which adenosine receptors is involved, we used specific agonists and inhibitors. We found that A1 receptor signaling was crucial for PMN function as inhibition or genetic ablation of A1 impaired the ability of PMNs from young mice to kill pneumococci. Importantly, activation of A1 receptors rescued the age-associated defect in PMN function. In exploring mechanisms, we found that PMNs from old mice failed to efficiently kill engulfed pneumococci and that A1 receptor controlled intracellular killing. In summary, targeting the EAD pathway reverses the age-driven decline in PMN antimicrobial function, which has serious implications in combating infections.