This article is Part I of a 3-part series from the 2015 Keystone Symposium on “Neuroinflammation in Diseases of the Central Nervous System”. To read all coverage from the meeting, click here.
Ponder, for a moment, the opening slide for the Keystone symposium “Neuroinflammation in Diseases of the Central Nervous System,” which ran January 25-30 in Taos, New Mexico. It defined neuroinflammation as “inflammation of a nerve or parts of the nervous system.” “When you need to use part of the word you’re defining to define it, then no one really knows what the word means,” joked Richard Ransohoff. The uncertainty epitomizes the field, which despite many years of research may only now be finding its groove. Three hundred attendees ascended to the high desert to share data and more thoroughly define and understand neuroinflammation. Co-organized by Ransohoff, who recently moved from the Cleveland Clinic in Ohio to Biogen IDEC in Cambridge, Massachusetts,Chris Glass of the University of California, San Diego, and V. Hugh Perry of the University of Southampton in England, this was the first Keystone symposium dedicated to neuroinflammation since 2005, when only 164 articles popped up on PubMed related to the topic. Last year, that number was 10 times higher, and the meeting pulsed with the energy of a rapidly changing field. Stay tuned in the coming days as Alzforum and ALS Forum bring you findings and controversies that engaged scientists at the meeting (see Part 2 and Part 3).
Amidst 27 oral presentations, 183 posters, and in conversation during meals, coffee breaks, and ski-lift rides, researchers grappled with how inflammation slows or hastens CNS disorders ranging from Alzheimer’s disease to multiple sclerosis, traumatic brain injury, viral infection, and stroke. Microglia and their monocyte cousins stole the show, as researchers aimed to more clearly understand what the brain’s in-house immune cells do, how they spring into action (or clam up) in the face of disease, and how they differ in form and function from infiltrating macrophages from other parts of the body.
Hunkered down at the Sagebrush Inn, once the home of the artist Georgia O’Keeffe, researchers painted a picture of complexity, sinking any hope of black-and-white explanations into the sienna desert mud. First and foremost, attendees tried to figure out what distinguishes microglia in the brain from other myeloid cells in the body. While circulating monocytes originate from progenitors in the bone marrow throughout a person’s lifetime, microglia derive from precursors that migrate from the yolk sac to the brain early in development. Once in the brain, these myeloid cells develop personalities uniquely suited to their new abode. As reported at the meeting, researchers uncovered combinations of transcription factors that buddy up and bind side-by-side to “super enhancer” regions in the genome to facilitate this specialization. These transcription factors were triggered by cues specific to each cell’s environment, and researchers reported that transferring macrophages into tissue culture dishes could to some extent undo their unique identities. How these signals might alter microglia in the aging or diseased brain was a hot topic at the meeting. Similarly, researchers reported that the gene expression profile of microglia and other macrophages changed dramatically in the context of diseases such as AD, ALS, and MS. While researchers made headway on distinguishing microglia from other macrophages at the level of gene expression, several attendees said it will be important to translate these genetic findings into functional ones.
At Keystone, researchers agreed it was time to bury the binary M1/M2 classification of pro-inflammatory and anti-inflammatory macrophages. There is consensus that, in vivo, pure M1 or M2 phenotypes, defined by the expression or lack of expression of specific genes, do not exist. Susanna Rosi of the University of California, San Francisco, reported that peripheral macrophages infiltrating the CNS after a traumatic brain injury, for example, express a variety of cytokines and do not adhere to strict M1 or M2 phenotypes. Christine Hsieh, also from UCSF, found no M1 or M2 profile in single cells extracted from the injury site following TBI. Perry received a round of applause when he said that adhering to the M1/M2 framework has held the field back, and that reviewers should no longer require researchers to consider this dichotomy. In many ways, the complexity of macrophage responses makes perfect biological sense, Perry told Alzforum. “You want diversity of function to respond to a diversity of insults. The last thing you want is for macrophages to behave in only one or two ways.” The tricky part, he added, is figuring out how to understand these complex behaviors in a coherent way.
Data about macrophage populations dovetailed with research on TREM2, clearly the most contentious molecule at the meeting. Some researchers reported that this cell surface receptor and AD risk factor predominantly shows up on microglia, while others claimed that infiltrating macrophages express most of the TREM2 in the brain. Researchers disagreed on TREM2’s role in the context of AD—some reported that plaque burden fell in TREM2-deficient mice, others that plaques stayed the same, and still others that plaques increased. TREM2 emerged as a potential survival signal for microglia as they fight off plaques, suggesting its loss could kill microglia and limit plaque clearance. A new idea emerged that lipids activate TREM2; this piqued widespread interest. It’s unclear whether this happens in the brain, and which lipids could do the trick; researchers speculated about apoptotic cells or even lipidated ApoE complexed with Aβ.
Researchers at the meeting also reported that microglia do more than just clean up debris; they play crucial roles in synaptic maintenance. Microglia are known to prune synapses during development, but recent findings suggest they do the same in the adult brain. At Keystone, researchers reported that complement proteins trigger microglia to target weaker synapses and that early synapse loss in AD mouse models depends on the complement system. Aβ oligomers switched this pruning into high gear. Intriguingly, a “don’t eat me” signal seems to protect some synapses, and researchers are studying whether this signal could become jumbled in neurodegenerative disease. PirB, a receptor for MHC I that is also activated by Aβ, keeps synaptic plasticity in check, and inhibiting it could be a way to boost flagging synapses.
The perennial chicken-or-egg question came up repeatedly: Is neuroinflammation a cause or consequence of neurodegenerative disease? At the meeting, researchers attempted to place neuroinflammation within a hierarchical framework with other pathologies. Drawing from a large cohort of AD patients, Chris Gaiteri of Rush University in Chicago combined gene-expression profiles with clinical data to create a network model of AD. He identified hubs represented by groups of genes with a common function (such as synaptic regulation), or by pathological characteristics (such as Aβ deposition). He then created a hierarchy based on the hubs that most affected other components of the network. Cytokines appeared near the top of the chain, followed by synaptic genes and cognitive decline, with tau and amyloid pathology skirting the bottom. While the prominence of neuroinflammatory hubs and the relative obscurity of Aβ and tau surprised some researchers, others felt that these complex network approaches were the way forward. “That’s where we’re going to define targets for intervention, and find insight into how systems work,” said Perry.
Perry’s talk moved the discussion below the neck, focusing on the importance of systemic inflammation as a driver of neurodegenerative disease. The neurodegenerative process primes microglia for action, and inflammatory signals from elsewhere in the body could kick the cells into high gear and exacerbate disease, he said. This relationship may prove important in the context of aging, where inflammatory diseases such as obesity and atherosclerosis could contribute to the problem. Perry presented results from a small trial that suggested treatment of AD patients with etanercept, a systemic inhibitor of TNF-α, may have slowed cognitive decline.
Genomic stability in neurons may also crumble with aging and incite chronic inflammation, suggested Mark Albers of Massachusetts General Hospital in Boston. He reported that double-stranded RNA (dsRNA), a product of botched DNA repair, multiply as neurons age and can trigger an inflammatory response. Albers stumbled upon the idea when he discovered that some APP transgenic mice developed neurodegeneration while others did not. In the former, copies of the transgene had inserted in opposite orientations, so they were transcribed in both sense and antisense directions, resulting in dsRNA. This duplex triggered a receptor called MDA5, an intracellular pattern-recognition receptor evolved to recognize viruses, and raised an inflammatory alarm. Albers proposed that this response—which can be triggered by any dsRNA—damages neurons. He pointed out that dsRNA commonly forms as a result of genetic inversions that occur during the DNA repair process in aging neurons. Glass was intrigued by the talk, but said that since this process would occur independently in each neuron, single-cell genomic sequencing would be the only way to measure it. He added that Albers had been selected to give a talk because his data was the most “out there.” After hearing the talk, Glass said it still was.
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