No abstract

Neurological disorders are major contributors to death and disability worldwide. The pathology of injuries and disease processes includes a cascade of events that often involve molecular and cellular components of the immune system and their interaction with cells and structures within the central nervous system. Because of this, there has been great interest in developing neuroprotective therapeutic approaches that target neuroinflammatory pathways. Several neuroprotective anti-inflammatory agents have been investigated in clinical trials for a variety of neurological diseases and injuries, but to date the results from the great majority of these trials has been disappointing. There nevertheless remains great interest in the development of neuroprotective strategies in this arena. With this in mind, the complement system is being increasingly discussed as an attractive therapeutic target for treating brain injury and neurodegenerative conditions, due to emerging data supporting a pivotal role for complement in promoting multiple downstream activities that promote neuroinflammation and degeneration. As we move forward in testing additional neuroprotective and immune-modulating agents, we believe it will be useful to review past trials and discuss potential factors that may have contributed to failure, which will assist with future agent selection and trial design, including for complement inhibitors. In this context, we also discuss inhibition of the complement system as a potential neuroprotective strategy for neuropathologies of the central nervous system.

Activation of the complement system propagates neuroinflammation and brain damage early and chronically after traumatic brain injury (TBI). The complement system is complex and comprises more than 50 components, many of which remain to be characterized in the normal and injured brain. Moreover, complement therapeutic studies have focused on a limited number of histopathological outcomes, which while informative, do not assess the effect of complement inhibition on neuroprotection and inflammation in a comprehensive manner. Using high throughput gene expression technology (NanoString), we simultaneously analyzed complement gene expression profiles with other neuroinflammatory pathway genes at different time points after TBI. We additionally assessed the effects of complement inhibition on neuropathological processes. Analyses of neuroinflammatory genes were performed at days 3, 7, and 28 post injury in male C57BL/6 mice following a controlled cortical impact injury. We also characterized the expression of 59 complement genes at similar time points, and also at 1- and 2-years post injury. Overall, TBI upregulated the expression of markers of astrogliosis, immune cell activation, and cellular stress, and downregulated the expression of neuronal and synaptic markers from day 3 through 28 post injury. Moreover, TBI upregulated gene expression across most complement activation and effector pathways, with an early emphasis on classical pathway genes and with continued upregulation of C2, C3 and C4 expression 2 years post injury. Treatment using the targeted complement inhibitor, CR2-Crry, significantly ameliorated TBI-induced transcriptomic changes at all time points. Nevertheless, some immune and synaptic genes remained dysregulated with CR2-Crry treatment, suggesting adjuvant anti-inflammatory and neurotropic therapy may confer additional neuroprotection. In addition to characterizing complement gene expression in the normal and aging brain, our results demonstrate broad and chronic dysregulation of the complement system after TBI, and strengthen the view that the complement system is an attractive target for TBI therapy.

The focus of this review is the role of complement-mediated phagocytosis in retinal and neurological diseases affecting the visual system. Complement activation products opsonize synaptic material on neurons for phagocytic removal, which is a normal physiological process during development, but a pathological process in several neurodegenerative diseases and conditions. We discuss the role of complement in the refinement and elimination of synapses in the retina and lateral geniculate nucleus, both during development and in disease states. How complement and aberrant phagocytosis promotes injury to the visual system is discussed primarily in the context of multiple sclerosis, where it has been extensively studied, although the role of complement in visual dysfunction in other diseases such as stroke and traumatic brain injury is also highlighted. Retinal diseases are also covered, with a focus on glaucoma and age-related macular degeneration. Finally, we discuss the potential of complement inhibitory strategies to treat diseases affecting the visual system.

Following traumatic brain injury (TBI), a neuroinflammatory response can persist for years and contribute to the development of chronic neurological manifestations. Complement plays a central role in post-TBI neuroinflammation, and C3 opsonins and the anaphylatoxins (C3a and C5a) have been implicated in promoting secondary injury. We used single cell mass cytometry to characterize the immune cell landscape of the brain at different time points after TBI. To specifically investigate how complement shapes the post-TBI immune cell landscape, we analyzed TBI brains in the context of CR2-Crry treatment, an inhibitor of C3 activation. We analyzed 13 immune cell types, including peripheral and brain resident cells, and assessed expression of various receptors. TBI modulated the expression of phagocytic and complement receptors on both brain resident and infiltrating peripheral immune cells, and distinct functional clusters were identified within same cell populations that emerge at different phases after TBI. In particular, a CD11c+ (CR4) microglia subpopulation continued to expand over 28 days after injury, and was the only receptor to show continuous increase over time. Complement inhibition affected the abundance of brain resident immune cells in the injured hemisphere and impacted the expression of functional receptors on infiltrating cells. A role for C5a has also been indicated in models of brain injury, and we found significant upregulation of C5aR1 on many immune cell types after TBI. However, we demonstrated experimentally that while C5aR1 is involved in the infiltration of peripheral immune cells into the brain after injury, it does not alone affect histological or behavioral outcomes. However, CR2-Crry improved post-TBI outcomes and reduced resident immune cell populations, as well as complement and phagocytic receptor expression, indicating that its neuroprotective effects are mediated upstream of C5a generation, likely via modulating C3 opsonization and complement receptor expression.