CD36-Mediated Hematoma Absorption following Intracerebral Hemorrhage: Negative Regulation by TLR4 Signaling

Abstract

Promoting hematoma absorption is a novel therapeutic strategy for intracerebral hemorrhage (ICH); however, the mechanism of hematoma absorption is unclear. The present study explored the function and potential mechanism of CD36 in hematoma absorption using in vitro and in vivo ICH models. Hematoma absorption in CD36-deficient ICH patients was examined. Compared with patients with normal CD36 expression, CD36-deficient ICH patients had slower hematoma adsorption and aggravated neurologic deficits. CD36 expression in perihematomal tissues in wild-type mice following ICH was increased, whereas the hematoma absorption in CD36−/− mice was decreased. CD36−/− mice also showed aggravated neurologic deficits and increased TNF-α and IL-1β expression levels. The phagocytic capacity of CD36−/− microglia for RBCs was also decreased. Additionally, the CD36 expression in the perihematoma area after ICH in TLR4−/− and MyD88−/− mice was significantly increased, and hematoma absorption was significantly promoted, which was significantly inhibited by an anti-CD36 Ab. In vitro, TNF-α and IL-1β significantly inhibited the microglia expression of CD36 and reduced the microglia phagocytosis of RBCs. Finally, the TLR4 inhibitor TAK-242 upregulated CD36 expression in microglia, promoted hematoma absorption, increased catalase expression, and decreased the H2O2 content. These results suggested that CD36 mediated hematoma absorption after ICH, and TLR4 signaling inhibited CD36 expression to slow hematoma absorption. TLR4 inhibition could promote hematoma absorption and significantly improve neurologic deficits following ICH.

RETRACTED: Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3β/PTEN axis

“…As described in our previous report, 22 after perfusion and fixation, the brains were removed and fixed for cutting on freezing microtome after they were embedded in O.C.T. Compound (Sakura).…”

“…21,22 Briefly, the mice were intraperitoneally anesthetized with 4% chloral hydrate and immobilized to a mouse stereotaxic frame. A total of 20 mL of non-anticoagulated autologous blood was obtained from the tail vein of the mouse and injected straight into the caudate nucleus (0.8 mm anterior, 2 mm left lateral and 3.5 mm deep relative to bregma).…”

A20 Ameliorates Intracerebral Hemorrhage–Induced Inflammatory Injury by Regulating TRAF6 Polyubiquitination

“…A20 in PBMCs plays a key role in inflammatory disease, but A20 expression in PBMCs differs across diseases. Increased A20 expression has been demonstrated in the PBMCs of patients with acute lymphoblastic leukemia and acute-on-chronic hepatitis B liver failure (ACHBLF) (23,24), whereas decreased A20 levels have been observed in the PBMCs of patients with chronic inflammatory diseases such as type-2 diabetes and SLE (12,25). However, the protective role of A20 is widely accepted, and its diverse expression in different diseases does not seem to be relevant to this role.…”

Neuronal Interleukin-4 as a Modulator of Microglial Pathways and Ischemic Brain Damage

“…By activating various pattern-recognition receptors, DAMPs propagate proinflammatory responses, primarily by activating neighboring microglia (Takeuchi and Akira, 2010). Proinflammatory mediators, proteases, and free radicals are ultimately elaborated, aggravating ischemia-mediated brain damage and even resulting in neuronal loss (Iadecola and Anrather, 2011; An et al, 2014).…”