Distinct migratory and cytokine responses of human microglia and macrophages to ATP

Abstract

Microglia and hematogenous myeloid cells are prominent components of inflammatory central nervous system (CNS) lesions associated with tissue injury. To help define the basis for recruitment of such cells into lesions and their contribution to the disease process, we characterized the migratory and cytokine responses of human adult and fetal microglia in the presence of extracellular ATP comparing them to monocytes and macrophages. Adult microglia showed increased migration in response to low ATP concentrations (1-10 μM) whereas fetal microglia also migrated in response to higher ATP dosages (100-300 μM). The enhanced migration of microglia was reproduced with 2-MeSADP, a P2Y1/12/13 agonist. In contrast, the chemokine CCL2 did not promote migration of microglia, but promoted the migration of monocytes. Monocyte migration was also enhanced with low concentrations of ATP, whereas higher concentrations of ATP mediated an inhibitory effect. ATP had only an inhibitory effect on macrophages, which was not reproduced with hydrolysis products ADP or adenosine. ATP led to a decrease in LPS-induced pro-inflammatory cytokine release (TNFα, IL-6) in both microglia and macrophages without suppression of an anti-inflammatory response (IL-10). These in vitro based results suggest that ATP can selectively favor the recruitment of microglia rather than hematogenous myeloid cells while promoting an anti-inflammatory state in both hematogenous and resident myeloid cells of the CNS. Our results highlight the importance of environmental signals in shaping the properties of the innate immune response to injury in the CNS.