Th180 - Myelin Has Less Suppressive Impacts on the Intracerebral Hemorrhage-relevant Alarmin S100A9 Than LPS

Abstract Text:

Introduction: During intracerebral hemorrhage (ICH), blood-derived macrophages that are stimulated by S100A9 produce cytokines that contribute to neuronal death. After three days, these macrophages turn reparative and become essential to tissue repair and recovery. This change in phenotype is poorly understood, but myelin has been implicated in suppressing the macrophage response to different inflammatory signals. Cholesterol, which is abundant in myelin, has been linked to the suppression of macrophages through the transcription factor LXR.
Methods and

Results: Murine bone marrow-derived macrophages were treated with myelin, cholesterol, or the LXR agonist T091317 for 18 hours. LPS and S100A9 were then used for stimulation for 6 hours. RNA sequencing data revealed that myelin suppressed inflammatory responses while also inducing a myelin-specific phenotype in macrophages. Secretion of TNF, IL-6, CCL2, and IL-10 was then measured. Myelin and cholesterol suppressed cytokine production during stimulation with LPS, but only to a lesser extent during S100A9 stimulation. T091317 could not suppress cytokine production with any stimulation. Dose titration revealed that neither myelin nor cholesterol suppressed the macrophage response to very high concentrations of LPS. Western blot demonstrated that cholesterol reduced phosphorylation of TLR4 signaling molecules during stimulation with LPS but not S100A9.

Conclusions: Myelin’s inability to suppress TNF production in response to S100A9 may explain why macrophages are neurotoxic in acute time points of ICH. Cholesterol’s inability to replicate myelin’s effects suggests other components of myelin may suppress macrophage responses during ICH.