Kinetics of proinflammatory monocytes in a model of multiple sclerosis and its perturbation by laquinimod.

Proinflammatory circulating monocytes have important roles in the pathology of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Yet there is limited information on their accumulation in blood during disease, the mechanisms that regulate their infiltration into the central nervous system (CNS), and whether medications affect their biology. We found a significant and prolonged elevation of CD11b(+)CCR2(+)Ly6C(high) proinflammatory monocytes in the blood of mice by the second day of immunization for EAE. At onset of clinical signs, levels of proinflammatory monocytes plummeted to those in naive mice. At day 16, when the majority of mice were at peak disease severity, clinical scores were inversely correlated to the proportion of proinflammatory monocytes in blood, and directly correlated with that in the spinal cord. Treatment with the MS medication laquinimod prevented EAE, correspondent with retention of proinflammatory monocytes in blood. The reduced entry of proinflammatory monocytes into the CNS by laquinimod was attributed to reduction of their levels of CD62L and matrix metalloproteinase-9. Moreover, the spinal cord of laquinimod-treated mice did not have elevated levels of CCR2 and CCL2, which provide chemotactic cues for monocytes. These results shed light on the important role of the trafficking of proinflammatory monocytes into the CNS to promote disease activity, and they identify a mechanism of action of laquinimod in MS.

Inflammatory monocytes facilitate adaptive CD4 T cell responses during respiratory fungal infection.

Aspergillus fumigatus, a ubiquitous fungus, causes invasive disease in immunocompromised humans. Although monocytes and antigen-specific CD4 T cells contribute to defense against inhaled fungal spores, how these cells interact during infection remains undefined. Investigating the role of inflammatory monocytes and monocyte-derived dendritic cells during fungal infection, we find that A. fumigatus infection induces an influx of chemokine receptor CCR2- and Ly6C-expressing inflammatory monocytes into lungs and draining lymph nodes. Depletion of CCR2(+) cells reduced A. fumigatus conidial transport from lungs to draining lymph nodes, abolished CD4 T cell priming following respiratory challenge, and impaired pulmonary fungal clearance. In contrast, depletion of CCR2(+)Ly6C(hi) monocytes during systemic fungal infection did not prevent CD4 T cell priming in the spleen. Our findings demonstrate that pulmonary CD4 T cell responses to inhaled spores require CCR2(+)Ly6C(hi) monocytes and their derivatives, revealing a compartmentally restricted function for these cells in adaptive respiratory immune responses.