MONTREAL—Macrophages and microglia represent rational targets in the treatment of patients with multiple sclerosis (MS), given that these cells are key effectors for tissue injury in inflammatory conditions in the CNS, said Samia J. Khoury, MD, at the 2008 World Congress on Treatment and Research in Multiple Sclerosis.
Therapies that inhibit microglial activation may be beneficial in chronic inflammatory diseases of the central nervous system such as MS. Potential inhibitors of microglia activation are peroxisome proliferator-activated receptor γ (PPAR-γ) agonists, anti-CD200 antibodies, and minocycline. Dr. Khoury discussed the role of reactive microglia in the initiation and propagation of immune responses as inflammatory mediators during inflammation in the CNS.
The acute MS lesion has been classically defined based on the presence of microglia ingesting myelin components and a lymphocyte inflammatory response. The chronic MS lesion, characteristic of the progressive phase of the disease, is dominated by the presence of activated microglia/macrophages without a prominent lymphocytic infiltrate. Human adult microglia can phagocytose myelin vesicles and secrete proinflammatory cytokines such as interleukin 1 (IL‑1), IL-6, and tumor necrosis factor α (TNF-α), and they are also known to undergo oxidative bursts. Diffuse injury of the normal-appearing white matter and cortical demyelination are classic hallmarks of primary and secondary progressive MS. The inflammation consists of mononuclear cells and diffuse infiltration of the tissue by T lymphocytes associated with profound activation of microglia.
Similar to patients with MS, the peak of disease activity in mice with experimental autoimmune encephalomyelitis (EAE)—a widely used animal model in MS—is characterized by T-cell infiltrates that decline during extended follow-up, whereas the microglia are activated persistently throughout the chronic phases. “This activation correlates well with the presence of cortical lesions, alteration of synaptic function, and axonal transport, each indicative of neuronal dysfunction,” said Dr. Khoury, Professor of Neurology at Brigham and Women’s Hospital in Boston. These data suggest that inflammation is sustained by microglia during the chronic phase of EAE.
The contribution of microglia to the progression of MS is evident in the following:
• Progressive MS correlates with the presence of diffuse axonal injury and activated microglia in the cortex and nonlesioned white matter.
• Increased expression of the major histocompatibility complex class II (MHC II) gene is found on microglia in nonlesioned white matter in the brains of patients with MS.
• Proinflammatory mediators released by microglia appear to be important contributors in blocking neurogenesis.
• Activation of microglia results in secretion of nitric oxide and proinflammatory cytokines such as IL-1, IL-6, IL-8, macrophage inflammatory protein 1-α, monocyte chemotactic protein 1, and TNF-α.
• Microglia in the subventricular zone proliferate and closely contact the neural stem cells.
Compounds that inhibit microglia activation include PPAR-γ agonists, anti-CD200 antibodies, and minocycline. PPAR-γ is a nuclear receptor that controls reproduction, metabolism, development, and immune responses. Natural and synthetic PPAR-γ agonists may control brain inflammation by inhibiting microglial activation, noted Dr. Khoury.
CD200 is expressed on neurons, and CD200R is expressed on macrophages/microglia. CD200-null mice experience an earlier onset of EAE, accompanied by an increased number and accumulation of activated macrophages and microglia in the CNS. After facial nerve transection, CD200-null mice have shown accelerated microglial response around neurons. Slow Wallerian degeneration mice have up-regulated CD200 and protection from EAE.
Minocycline has been shown to ameliorate EAE by peripheral immunomodulatory properties. Its mechanisms of action include inhibition of matrix metalloproteinase 2 activity and inhibition of inducible nitric oxide synthase, prostaglandin-E2, caspase-1, caspase-3, and cyclo-oxygenase–2 expressions, as well as the impairment of cytokine production. Some of these mechanisms are manifested, at least in part, by inhibition of mitogen-activated protein kinases. Minocycline also inhibits protein kinase C activation and decreases MHC II expression.