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Kinetics of proinflammatory monocytes in a model of multiple sclerosis and its perturbation by laquinimod
Manoj K Mishra1, Janet Wang, Claudia Silva
1Hotchkiss Brain Institute and the University of Calgary, Calgary, Alberta, Canada.
Abstract:
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.
Insights
Proinflammatory monocytes in the blood are crucial for multiple sclerosis (MS) pathology. The drug laquinimod retains these monocytes in the blood, preventing their entry into the central nervous system (CNS) and reducing disease severity.
Area of Science:
- Immunology
- Neuroscience
- Pharmacology
Background:
- Proinflammatory monocytes are implicated in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) pathogenesis.
- Limited data exists on monocyte blood accumulation, CNS infiltration mechanisms, and medication effects in MS/EAE.
Purpose of the Study:
- To investigate the dynamics of proinflammatory monocyte accumulation in blood during EAE.
- To elucidate the mechanisms regulating monocyte CNS infiltration.
- To determine the impact of laquinimod on monocyte biology and EAE progression.
Main Methods:
- Monitoring CD11b(+)CCR2(+)Ly6C(high) proinflammatory monocytes in mouse blood and spinal cord during EAE.
- Correlating monocyte levels with clinical EAE scores.
- Assessing the effects of laquinimod treatment on monocyte trafficking and CNS markers.
Main Results:
- EAE induction led to a transient increase in blood proinflammatory monocytes, followed by a decrease at clinical onset.
- Peak EAE severity correlated inversely with blood monocytes and directly with spinal cord monocytes.
- Laquinimod treatment prevented EAE, retaining monocytes in blood and reducing their CNS infiltration by downregulating CD62L and matrix metalloproteinase-9.
- Laquinimod also reduced CNS expression of monocyte chemoattractants CCR2 and CCL2.
Conclusions:
- Proinflammatory monocyte trafficking into the CNS is critical for MS/EAE disease activity.
- Laquinimod exerts therapeutic effects by inhibiting monocyte CNS entry.
- This study reveals a key mechanism of action for laquinimod in MS treatment.
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