Signalling pathways mediating inflammatory responses in brain ischaemia

Abstract

Stroke causes neuronal necrosis and generates inflammation. Pro-inflammatory molecules intervene in this process by triggering glial cell activation and leucocyte infiltration to the injured tissue. Cytokines are major mediators of the inflammatory response. Pro-inflammatory and anti-inflammatory cytokines are released in the ischaemic brain. Anti-inflammatory cytokines, such as interleukin-10, promote cell survival, whereas pro-inflammatory cytokines, such as TNFalpha (tumour necrosis factor alpha), can induce cell death. However, deleterious effects of certain cytokines can turn to beneficial actions, depending on particular features such as the concentration, time point and the very intricate network of intracellular signals that become activated and interact. A key player in the intracellular response to cytokines is the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathway that induces alterations in the pattern of gene transcription. These changes are associated either with cell death or survival depending, among other things, on the specific proteins involved. STAT1 activation is related to cell death, whereas STAT3 activation is often associated with survival. Yet, it is clear that STAT activation must be tightly controlled, and for this reason the function of JAK/STAT modulators, such as SOCS (suppressors of cytokine signalling) and PIAS (protein inhibitor of activated STAT), and phosphatases is most relevant. Besides local effects in the ischaemic brain, cytokines are released to the circulation and affect the immune system. Unbalanced pro-inflammatory and anti-inflammatory plasma cytokine concentrations favouring an 'anti-inflammatory' state can decrease the immune response. Robust evidence now supports that stroke can induce an immunodepression syndrome, increasing the risk of infection. The contribution of individual cytokines and their intracellular signalling pathways to this response needs to be further investigated.

Leptin in the hindbrain facilitates phosphorylation of STAT3 in the hypothalamus

“…Although pSTAT3 is an accepted marker of ObRb activation, there are other factors, such as serotonin and proinflammatory cytokines (IL-1, IL-6, and TNF), present in the brain that can also activate STAT3 (13,38). Our results show that the pSTAT3 immunoreactivity distribution associated with chronic leptin infusion is restricted to nuclei expressing ObRbs, and, thus, we assume that it is most likely an effect of ObRb activation.…”

Evidence that γ-Secretase-Mediated Notch Signaling Induces Neuronal Cell Death via the Nuclear Factor-κB-Bcl-2-Interacting Mediator of Cell Death Pathway in Ischemic Stroke

“…3C) or Z-VAD significantly ameliorated cell death induced by NICD. Key players in the intracellular response to ischemic stroke are kinase pathways that induce alterations in the pattern of gene transcription (Planas et al, 2006). To examine the contribution of kinases to Notch-induced cell death, we tested the effects of several kinase inhibitors (data not shown).…”

Mast Cells Are Early Responders After Hypoxia-Ischemia in Immature Rat Brain

“…[27][28][29] Several studies have investigated the cellular, biochemical, and molecular responses to cerebral ischemia in adult 30 and immature nervous systems 4,5,31 to determine which cells might be the most appropriate targets to inhibit the inflammatory cascade. No previous study has included brain mast cells in this analysis The current experiments tested 2 hypotheses: (1) MCs are the first cells to respond to HI in immature brain; (2) inhibition of this early MC response is sufficient to provide long-term protection.…”