Tissue-resident microglia and recruited monocytes: relevance in neuroinflammation after peripheral lipopolysaccharide challenge

PERALTA RAMOS, JM; BUSSI, C; GAVIGLIO, EA; IRIBARREN, P; ARROYO, DS

Keystone

Congreso; Keystone Symposia Microglia in the brain; 2016

Keystone Research Conferences

Brain-resident microglia (Mi) and blood-derived monocytes, playessential roles in shaping the immune response in the central nervous system.These cells activate and migrate in response to chemokines produced during activeimmune responses and may contribute to the progression of neuroinflammation. Inthis study, we investigated the phenotypic and functional profile oftissue-resident microglia and recruited inflammatory monocytes (InfMo), tounderstand the contribution of each population in the establishment anddevelopment of a neuroinflammatory process induced by systemic TLR4 stimulation.We characterized the molecular and cellular players involved inneuroinflammation induced by lipopolysaccharide (LPS - 1.6 mg/kg) i.p. administrationto C57BL/6 mice using flow cytometry combined with ex-vivo functional essays and confocal microscopy. Followingstimulation with LPS, we found increased absolute number (p<0.001) of activated CD11b+CD45low Mi and CD11b+ CD45highLy6Chigh InfMo populations with differential production of  cytokines IFN-γ (Th1), IL-17 (Th17) and IL-4 (Th2)(p<0.05) and membrane/intracellular expression of chemokine receptors CCR2+ and CX3CR1+ (p<0.001) compared with vehicle treated-mice. We next found InfMopurified by cell sorting suppressed CD4+ and CD8+T cell proliferation (p<0.05) but that this response was restored whencells were primed ex-vivo with LPS (100ng/ml) plus IFN-γ (20 ng/ml). Furthermore, aminoguanidine (90 uM), a nitricoxide inhibitor, enhanced T cell proliferation (p<0.01). Together, systemic stimulationof TLR4 would modulate chemokine receptors which are key for the recruitment ofleukocytes in a neuroinflammatory response. These findings highlights the differencesbetween tissue-resident versus peripheral recruited cells in an inflamed microenvironment.