Dealing with Danger in the CNS: The Response of the Immune System to Injury

Abstract

Fighting pathogens and maintaining tissue homeostasis are prerequisites for survival. Both of these functions are upheld by the immune system, though the latter is often overlooked in the context of the CNS. The mere presence of immune cells in the CNS was long considered a hallmark of pathology, but this view has been recently challenged by studies demonstrating that immunological signaling can confer pivotal neuroprotective effects on the injured CNS. In this review, we describe the temporal sequence of immunological events that follow CNS injury. Beginning with immediate changes at the injury site, including death of neural cells and release of damage-associated molecular patterns (DAMPs), and progressing through innate and adaptive immune responses, we describe the cascade of inflammatory mediators and the implications of their post-injury effects. We conclude by proposing a revised interpretation of immune privilege in the brain, which takes beneficial neuro-immune communications into account.

Figure 1. Kinetics of the molecular and cellular immune response to CNS injury

(A) The phases of molecular and cellular inflammation after CNS injury. Danger-associated molecular patterns (DAMPs) such as IL-33, HMGB1 and ATP are released immediately following CNS injury. The inflammasome is activated soon after and produces IL-1β and IL-18. Neutrophils arrive hours after injury and stay for several days, while monocytes begin infiltrating within the first day and remain present. Lymphocytes begin to arrive days to weeks post-injury. (B) Specific inflammatory molecules active at each time post injury are listed.

Figure 2. Necrotic cell death causes the release alarmins into the extracellular space

Necrotic cell death releases peptide and nucleic acid derivative alarmins that initiate inflammation. IL-33 plays an important role in bringing monocyte-derived macrophages into the CNS through upregulation of astrocytic chemokine expression. ATP promotes chemotaxis of neutrophils (through its activation of the inflammasome), and is directly chemotactic to microglial processes. ATP and uric acid also activates the inflammasome, stimulating the assembly of the cytosolic NLR, ASC, and pro-caspase 1. Pro-caspase 1 is auto-cleaved to mature caspase 1, which cleaves pro-IL-1β and pro-IL-18 to active forms and IL-33 to an inactive form. HMGB1 acts as on TLR4 and RAGE receptors and directly promotes inflammatory cytokine and chemokine production. An important transcription factor downstream of both receptors is NF-κB, important in enhancing inflammation and cellular infiltration, but the RAGE receptor has several other downstream signaling pathways (not shown here). IL-1α and uric acid (gray arrows), are important inducers of immune responses in response to tissue damage in the periphery, however their roles in response to CNS injury remained poorly defined.

Figure 3. Beneficial and detrimental roles for macrophages and neutrophils in CNS injury

Macrophages and neutrophils have been described to promote both beneficial and detrimental outcomes following CNS injury. Whether these cells orchestrate CNS repair or exacerbate tissue damage following CNS trauma depends on the specific factors that are generated. Beneficial roles for macrophages (top left) in the CNS include their ability to clear cell debris and produce growth factors and other protective molecules including BDNF, GDNF and IL-10. Detrimental roles for macrophages (top right) include production of glutamate and through contact-mediated axon dieback. Both macrophages and neutrophils beneficially produce the atypical growth factor oncomodulin and clear pathogens in non-sterile injuries (left), and detrimentally produce the free radical nitric oxide (right). Neutrophils additionally secrete the enzyme elastase, which was shown to be detrimental following injury (right).