Is there a scenario in which neuroinflammation can actually heal?

Neuroinflammation is held accountable for neurodegenerative disease onset and/or progression because cells involved in pathological processes release pro-inflammatory and cytotoxic agents causing neuronal cell death. But what if that is not the whole story? After all, it is a natural process of the body in response to a harmful event, so is there a scenario in which neuroinflammation can actually heal?

Traumatic spinal cord injuries (SCI) cause sensorimotor function loss because the physical insult destroys the nervous tissue, interrupting the flow of information to and from the brain. The impact on the spinal cord induces death to local neurons and glia within minutes to hours, defining the primary damage phase.

Trying to counteract the injury, the so-called secondary damage phase shall be carried out. During this phase a series of cellular and molecular events occur immediately after the insult and persist for months to years, giving rise to neuroinflammatory response. This phase should limit the damage and facilitate recovery processes, but it can appear responsible for damage to uninvolved neural areas and further loss.

On the one hand the inflammatory response during the second phase is crucial for the clearance of tissue debris, microglia activation, immune cell infiltration, and curbing the cell death area by the glial scar formation (astrocytes). On the other hand, the proinflammatory agents secreted by microglia and astrocytes are harmful for healthy tissue, and neuroinflammation negatively interferes with recovery mechanisms and exacerbates the damage.

Different events are involved in SCI secondary damage including uncontrolled oxidative stress, ischemia and glutamate-mediated excitotoxicity, which are phenomena that cause cell death. Moreover the formation of glial scars surrounding the necrotic part of the injury epicentre represents a physical barrier that hampers the neural function and axonal regeneration.

Numerous studies that have attempted to suppress one or more key elements of neuroinflammation have failed in SCI recovery. Studies that have tried to use only stem cells for regeneration, without taking into consideration neuroinflammation, have failed and in some cases have worsened the situation.

Perhaps the best way is a controlled neuroinflammation, i.e. a selective modulation of key factors in time-dependent way to preserve uninjured tissue and to create a hospitable environment for stem cells to graft or to stimulate stem cells activation and differentiation from spinal niches (endogenous cell pool).

Can this be the future we are looking for?

Dr. Sara Martinelli, PhD, is a scientist at the National Research Council, Istituto di Biochimica e Biologia Cellulare, Rome.