The complex contribution of chemokines to neuroinflammation: switching from beneficial to detrimental effects

Abstract

Inflammation is an innate mechanism that defends organisms against harmful stimuli. Inflammation leads to the production and secretion of proinflammatory mediators that activate and recruit immune cells to damaged tissues, including the brain, to resolve the cause of inflammation. In the central nervous system, inflammation is referred to as neuroinflammation, which occurs in various pathological conditions of the brain. The primary role of neuroinflammation is to protect the brain. However, prolonged and/or inappropriate inflammation can be harmful for the brain, from individual cells to the whole tissue. This review focuses on a particular type of inflammatory mediator, chemokines, and describes their complex effects both under physiological and pathophysiological conditions of the brain. The clinical relevance of the multiple characters of chemokines is highlighted with respect to acute and chronic inflammation of the brain, including their actions in stroke and Alzheimer's disease, respectively.

Sterile Neuroinflammation and Strategies for Therapeutic Intervention

“…Under normal physiological conditions in the brain, chemokines acting on microglia and astrocytes contribute to physiological processes, such as memory, learning, synapse formation, and brain development. Chemokines engage mainly in chemotaxis that are involved in CNS development and homeostatic migration and turnover of cells such as neural precursors in the adult brain [81]. On the other hand during infection or injury, the main change in chemokines is their increased expression level and the most described feature is the chemoattraction of immune cells from the periphery to the brain parenchyma via BBB (Figure 1) [81].…”

“…Chemokines engage mainly in chemotaxis that are involved in CNS development and homeostatic migration and turnover of cells such as neural precursors in the adult brain [81]. On the other hand during infection or injury, the main change in chemokines is their increased expression level and the most described feature is the chemoattraction of immune cells from the periphery to the brain parenchyma via BBB (Figure 1) [81]. The infiltrated peripheral cells maintain inflammation through cytokine and chemokine secretion, activating resident microglia and astrocytes.…”

“…The recruitment and overactivation of such cell types can become deleterious for neuronal survival and function. CX3CL1 or fractalkine/neurotactin, CCL2 or monocyte chemoattractant protein-1, and CXCL12 or stromal cell-derived factor-1 are the three most studied chemokines in the adult CNS [81]. …”

Role of neuroinflammation in ischemic stroke

“…[51,52] On the contrary, the negative aspects of neuroinflammation mainly represent maladaptive inflammatory responses. [53,54] The common characteristics of this aspect is increasing, supraphysiological production of cytokines [IL-1 and tumor necrosis factor (TNF)], ROS, and other inflammatory mediators including inducible nitric oxide synthase. [55] These markers are highly evident in the high traumatic CNS, giving rise to collateral damage.…”

Neutralizing anti-interleukin-1β antibodies reduce ischemia-related interleukin-1β transport across the blood–brain barrier in fetal sheep

“…In adult rats, the IL-1 receptor antagonist, IL-1RA reduced brain injury induced by focal cerebral ischemia (Clark et al, 2008). Nonetheless, inflammation can have both beneficial and detrimental effects in the brain after injury (Le Thuc et al, 2015), therefore, the effects of the anti-IL-1β mAb on the neuropathological changes after brain ischemia in fetal sheep brain remain to be determined. However, based upon the recent findings in adult rodents (Clark et al, 2008, Denes et al, 2011, Maysami et al, 2016), it appears that inhibition of IL-1β transport across the BBB could potentially ameliorate perinatal brain injury.…”