Impaired Blood Dendritic Cell Numbers and Functions after Aneurysmal Subarachnoid Hemorrhage

Abstract

Previous PresentationPortions of this study were presented at the Annual Congress of Société Française d’Anesthésie et de Réanimation in Paris, September 2012.BackgroundToll-like receptor (TLR) agonists are promising therapy for the prevention of nosocomial infections in critical ill patients. We aimed to analyze the TLR-reactivity of circulating dendritic cells (DC) as assessed by cytokine production after an ex vivo challenge with TLR agonists in aneurysmal subarachnoid hemorrhage (SAH) patients.Methods and FindingsA single-center prospective observational study took place in one intensive care unit of a teaching hospital. Blood samples were harvested on days 2, 5 and 10 in 21 severe SAH patients requiring mechanical ventilation and 17 healthy controls. DC production of cytokines (Tumour Necrosis Factor, TNF-α; Interleukin, IL-12; and Interferon, IFN-α) was assessed by intracellular immunostaining on TLR-3, 4, 7/8 and 9 stimulations. SAH patients had decreased numbers of blood myeloid (mDCs) and plasmacytoid DCs (pDCs) on days 2, 5 and 10. Compared with the healthy controls, the frequency of mDCs producing TNF-α after TLR-3 stimulation was decreased in the SAH patients. The frequency of myeloid DCs producing IL-12 after TLR-3 and 4 stimulations was also decreased in the SAH patients. In contrast, the mDCs response to TLR-7/8 was not impaired in the SAH patients. The frequency of pDCs producing TNF-α+ and IFN-α+ on TLR-7/8 stimulation were reduced at all of the tested times in the SAH patients, whereas reactivity to TLR-9 was preserved. On day 2, the pDCs from non-survivor patients (n = 8) had a decreased ability to produce IFN-α on TLR-9 stimulation compared with the survivors.ConclusionsThese data suggest functional abnormalities of circulating pDCs and mDCs that could be important for immunomodulation after SAH.

Sepsis-associated encephalopathy: a vicious cycle of immunosuppression

“…The number of circulating DCs was significantly lower in patients suffering from aneurysmal subarachnoid hemorrhage compared to that of healthy controls [50]. These DCs exhibited a remarkable anergic response to Toll-like receptor (TLR)3 and TLR4 stimulation, as evidenced by diminished production of TNF-α and IL-2, suggesting that aneurysmal subarachnoid hemorrhage-induced brain dysfunction compromised the function and viability of DCs [50]. Yilmaz and colleagues found that circulating DC precursors underwent transient decrease after acute stroke, which was correlated with the severity of brain injury [51].…”

“…Monocytes/macrophages Decreasing the number of monocytes; polarization of M2 phenotype; increasing production of IL-10; reducing phagocytic capability [43], [44], [45] Neutrophils Impairment in ROS production; reduction of phagocytosis; shortening life-span as a result of spontaneous apoptosis [43,[46][47][48][49] Dendritic cells Decreasing number of circulating DCs; anergic response to TLR3 and TLR4 stimulations; incapable of priming effective cellular immune response; disturbed infiltration and aberrant phenotypic differentiation [50][51][52][53] T lymphocytes Reducing proportion of peripheral T cells; disturbing response to antigens; polarization of anti-inflammatory phenotypes; inducing imbalance between Tregs and proinflammatory phenotypes of T cells [54][55][56][57][58] sepsis, but they are rarely found in the normal brain [66]. Neutrophils accumulating in the central nervous system jeopardize brain cells by releasing inflammatory cytokines, increasing the activity of myeloperoxidase, and promoting oxidative damage [74].…”

“…In patients with severe head injury, for example, the host response to common antigens showed significant suppression, along with a marked increase in opportunistic infections [85]. The number of circulating DCs was significantly lower in patients suffering from aneurysmal subarachnoid hemorrhage compared to that of healthy controls [50]. These DCs exhibited a remarkable anergic response to Toll-like receptor (TLR)3 and TLR4 stimulation, as evidenced by diminished production of TNF-α and IL-2, suggesting that aneurysmal subarachnoid hemorrhage-induced brain dysfunction compromised the function and viability of DCs [50].…”

Trauma-Induced Damage-Associated Molecular Patterns-Mediated Remote Organ Injury and Immunosuppression in the Acutely Ill Patient

“…After massive DAMP release, the early overwhelming inflammatory response can further leave an immunological scar that will be responsible for protracted immune alterations (IS) ( 84 ) and will worsen patient outcome. This IS decreases the capacity of monocytes to produce inflammatory cytokines after TLR stimulation ( 52 , 85 , 86 ) and APC to prime antigen on type 2 MHC molecules. Austermann et al highlighted that MRP linkage with TLRs induced phagocyte hyporesponsiveness to subsequent TLR agonist stimulation and was correlated with poor outcome ( 45 ).…”

The role of Toll-like receptor signaling pathways in cerebrovascular disorders: the impact of spreading depolarization

“…The frequency of myeloid dendritic cells producing TNF-α after application of TLR-3 agonist poly I:C significantly decreased in the SAH patients. In addition, myeloid dendritic cells producing administration of TLR-3 and 4 agonists decreased in the SAH patients compared to healthy subjects [137].…”