Inflammation and immune cell abnormalities in intracranial aneurysm subarachnoid hemorrhage (SAH): Relevant signaling pathways and therapeutic strategies

Abstract

Intracranial aneurysm subarachnoid hemorrhage (SAH) is a cerebrovascular disorder associated with high overall mortality. Currently, the underlying mechanisms of pathological reaction after aneurysm rupture are still unclear, especially in the immune microenvironment, inflammation, and relevant signaling pathways. SAH-induced immune cell population alteration, immune inflammatory signaling pathway activation, and active substance generation are associated with pro-inflammatory cytokines, immunosuppression, and brain injury. Crosstalk between immune disorders and hyperactivation of inflammatory signals aggravated the devastating consequences of brain injury and cerebral vasospasm and increased the risk of infection. In this review, we discussed the role of inflammation and immune cell responses in the occurrence and development of aneurysm SAH, as well as the most relevant immune inflammatory signaling pathways [PI3K/Akt, extracellular signal-regulated kinase (ERK), hypoxia-inducible factor-1α (HIF-1α), STAT, SIRT, mammalian target of rapamycin (mTOR), NLRP3, TLR4/nuclear factor-κB (NF-κB), and Keap1/nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/ARE cascades] and biomarkers in aneurysm SAH. In addition, we also summarized potential therapeutic drugs targeting the aneurysm SAH immune inflammatory responses, such as nimodipine, dexmedetomidine (DEX), fingolimod, and genomic variation-related aneurysm prophylactic agent sunitinib. The intervention of immune inflammatory responses and immune microenvironment significantly reduces the secondary brain injury, thereby improving the prognosis of patients admitted to SAH. Future studies should focus on exploring potential immune inflammatory mechanisms and developing additional therapeutic strategies for precise aneurysm SAH immune inflammatory regulation and genomic variants associated with aneurysm formation.

Decoding the biology and clinical implication of neutrophils in intracranial aneurysm

“…Vascular cell sparsity is the feature of IA 2 . One of the main causes is the loss of SMC induced by various factors, such as inflammation 13,14,50 . Despite the destructive nature of neutrophil‐induced inflammation on the IA wall, 19 the mechanisms by which these cells regulate the status of SMCs remain unclear.…”

“… 2 One of the main causes is the loss of SMC induced by various factors, such as inflammation. 13 , 14 , 50 Despite the destructive nature of neutrophil‐induced inflammation on the IA wall, 19 the mechanisms by which these cells regulate the status of SMCs remain unclear. We dismantled the complicated neutrophil‐SMC communications based on both human and murine scRNA‐Seq datasets.…”

Morphometric Study of the Initial Ventricular Indices to Predict the Complications and Outcome of Aneurysmal Subarachnoid Hemorrhage

“…The occurrence and severity of these outcome-relevant pathophysiologic processes depends, at least partially, on the extent of the local and systemic inflammatory responses to the aneurysmal bleeding and the subsequent early brain injury [ 22 ]. Neuroinflammation within the brain is driven by inflammatory cells, both those that are locally present and circulating peripherally, and mediated by reactive oxygen species, cytokines, chemokines and other messenger molecules [ 23 , 24 , 25 ].…”

Targeting brain-peripheral immune responses for secondary brain injury after ischemic and hemorrhagic stroke

“…In addition, Tregs also protect against BBB damage, which is mainly achieved by inhibiting peripheral MMP-9 production [ 343 ]. These findings show that the role of T cells in the development of inflammation is bidirectional, as cytokines can both eliminate damaged cells and clear microorganisms, leading to a severe inflammatory cascade [ 344 , 345 ]. Angiogenesis is an important repair mechanism after stroke, and the effect of T cells on angiogenesis has been demonstrated in numerous organs.…”