ABSTRACT
The surface of the central nervous system (CNS) is protected by the meninges, which contain a dense network of meningeal macrophages (MMs). Here, we examined the role of tissue-resident MM in viral infection. MHC-II- MM were abundant neonatally, whereas MHC-II+ MM appeared over time. These barrier macrophages differentially responded to in vivo peripheral challenges such as LPS, SARS-CoV-2, and lymphocytic choriomeningitis virus (LCMV). Peripheral LCMV infection, which was asymptomatic, led to a transient infection and activation of the meninges. Mice lacking macrophages but conserving brain microglia, or mice bearing macrophage-specific deletion of Stat1 or Ifnar, exhibited extensive viral spread into the CNS. Transcranial pharmacological depletion strategies targeting MM locally resulted in several areas of the meninges becoming infected and fatal meningitis. Low numbers of MHC-II+ MM, which is seen upon LPS challenge or in neonates, corelated with higher viral load upon infection. Thus, MMs protect against viral infection and may present targets for therapeutic manipulation.
Subject(s)
COVID-19 , Lymphocytic Choriomeningitis , Animals , Mice , Lipopolysaccharides , Mice, Inbred C57BL , SARS-CoV-2 , Lymphocytic choriomeningitis virus/physiology , Macrophages , MeningesABSTRACT
BACKGROUND: COVID-19 is still a worldwide pandemic and extracorporeal membrane oxygenation (ECMO) is vital for extremely critical COVID-19 patients. Pulsatile flow impacts greatly on organ function and microcirculation, however, the effects of pulsatile flow on hemodynamics and inflammatory responses during ECMO are unknown. An in vivo study was launched aiming at comparing the two perfusion modes in ECMO. METHODS: Fourteen beagles were randomly allocated into two groups: the pulsatile group (n=7) and the non-pulsatile group (n=7). ECMO was conducted using the i-Cor system for 24 hours. Hemodynamic parameters including surplus hemodynamic energy (SHE), energy equivalent pressure (EEP), oxygenator pressure drop (OPD), and circuit pressure drop (CPD) were monitored. To assess inflammatory responses during ECMO, levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6, IL-8, and transforming growth factor-ß1 (TGF-ß1) were measured. RESULTS: EEP and SHE were markedly higher in pulsatile circuits when compared with the conventional circuits. Between-group differences in both OPD and CPD reached statistical significance. Significant decreases in TNF-α were seen in animals treated with pulsatile flows at 2 hours, 12 hours, and 24 hours as well as a decrease in IL-1ß at 24 hours during ECMO. The TGF-ß1 levels were significantly higher in pulsatile circuits from 2 hours to 24 hours. The changes in IL-6 and IL-8 levels were insignificant. CONCLUSION: The modification of pulsatility in ECMO generates more hemodynamic energies and attenuates inflammatory responses as compared to the conventional non-pulsatile ECMO.