Mast Cells Mediate Inflammatory Injury and Aggravate Neurological Impairment in Experimental Subarachnoid Hemorrhage Through Microglial PAR-2 Pathway

Abstract

Subarachnoid hemorrhage (SAH) is a devastating cerebrovascular disease with high mortality and disability. Aberrant neuroinflammation has been identified as a critical factor accounting for the poor prognosis of SAH patients. Mast cells (MCs), the sentinel cells of the immune system, play a critical in the early immune reactions and participate in multiple pathophysiological process. However, the exact role of MCs on the pathophysiological process after SAH has not been fully understood. The current study was conducted to determine the role of MCs and MC stabilization in the context of SAH. Mouse SAH model was established by endovascular perforation process. Mice received saline or cromolyn (MC stabilizer) or compound 48/80 (MCs degranulator). Post-SAH evaluation included neurobehavioral test, western blot, immunofluorescence, and toluidine blue staining. We demonstrated that SAH induced MCs activation/degranulation. Administration of MC stabilizer cromolyn conferred a better neurologic outcome and decreased brain edema when compared with SAH+vehicle group. Furthermore, cromolyn significantly inhibited neuroinflammatory response and alleviated neuronal damage after SAH. However, pharmacological activation of MCs with compound 48/80 dramatically aggravated SAH-induced brain injury and exacerbated neurologic outcomes. Notably, pharmacological inhibition of microglial PAR-2 significantly reversed MCs-induced inflammatory response and neurological impairment. Additionally, the effect of MCs-derived tryptase in mediating neuroinflammation was also abolished by the microglial PAR-2 blockage in vitro. Taken together, MCs yielded inflammatory injury through activating microglia-related neuroinflammation after SAH. These data shed light on the notion that MCs might be a novel and promising therapeutic target for SAH.

Sinomenine Protects against Early Brain Injury by Inhibiting Microglial Inflammatory Response via Nrf2-Dependent Pathway after Subarachnoid Hemorrhage

“…The inflammatory response is an important step in EBI, which is induced by neuronal necrotic products and hemoglobin degradation products, and stimulates microglia activation after SAH [20]. The activated microglia amplify the inflammatory response, the principle macrophages of the central nervous system, releasing various inflammatory factors and chemokines that further promote neuronal damage [21]. Abundant evidence suggests that microglial activation and the subsequent neuroinflammatory response participates in EBI [22,23].…”

Role of microglia after subarachnoid hemorrhage

“…82 It has been suggested that mast cells play a pivotal role in early responses to aneurysm rupture by organizing the microglial response. 83 After local mast cells recognize blood-derived toxins, they rapidly degranulate and secrete tryptase, which binds to the Protease-activated receptor 2 (PAR-2) receptor on microglia, activating microglia and promoting the secretion of TNF-α, IL-1β, and IL-6. 83 Microglia then communicate with additional peripheral leukocytes.…”

“…83 After local mast cells recognize blood-derived toxins, they rapidly degranulate and secrete tryptase, which binds to the Protease-activated receptor 2 (PAR-2) receptor on microglia, activating microglia and promoting the secretion of TNF-α, IL-1β, and IL-6. 83 Microglia then communicate with additional peripheral leukocytes. Chemokines produced by microglia recruit neutrophils and monocytes from the periphery that transmigrate through the compromised BBB and enter the CNS.…”

“…Chemokines produced by microglia recruit neutrophils and monocytes from the periphery that transmigrate through the compromised BBB and enter the CNS. 83 Neutrophils specifically have garnered greater attention as effectors of neuroinflammation during the EBI period based on two critical pieces of evidence. First, neutrophils have been observed entering the CNS as early as 10 minutes after experimental SAH, and may partake in the development of secondary brain injury at an early time.…”

Activation of Mast Cells by Neuropeptides: The Role of Pro-inflammatory and Anti-Inflammatory Cytokines

“…MCs secrete neuropeptides CRH and Substance P (SP), which activate microglia in the brain to generate IL-1 and the chemokines CXCL8 (34). In fact, MCs cross-talk with microglia by releasing histamine and tryptases which induce the secretion of pro-inflammatory cytokines in MCs (35).…”