Biliverdin reductase-A attenuated GMH-induced inflammatory response in the spleen by inhibiting toll-like receptor-4 through eNOS/NO pathway

Yiting Zhang,Devin W Mcbride,Tai Lu,John H Zhang,Yixin Zhang,Jiping Tang,Yan Ding,Ningbo Xu

doi:10.1186/s12974-018-1155-z

Abstract

BackgroundGerminal matrix hemorrhage (GMH) is a common neurologic event with high morbidity and mortality in preterm infants. Spleen has been reported to play a critical role in inflammatory responses by regulating peripheral immune cells which contributes to secondary brain injury.MethodsThe current study investigated the mechanistic role of biliverdin reductase-A (BLVRA) in the splenic response and brain damage in neonates following a collagenase GMH model. Neurological outcomes and splenic weights were assessed. Neutrophil production and infiltration were quantitated in the spleen and brain, respectively. Western blot was performed in both splenic and brain tissues to measure protein levels of toll-like receptor 4 and proinflammatory cytokines.ResultsBLVRA treatment alleviated GMH-induced developmental delay and attenuated splenic atrophy at 1 and 3 days after GMH. Quantification analysis showed that spleen-stored peripheral immune cells mobilized into circulation and infiltrated in the brain following GMH, which was abrogated by BLVRA administration, resulting in reduced splenic inflammatory response. Furthermore, we showed that regulation of eNOS/NO signaling by BLVRA stimulation blunted toll-like receptor-4 (TLR4) signal. The eNOS-generated NO, in part, translocated BLVRA into the nucleus, where BLVRA inhibited TLR4 expression.ConclusionWe revealed a BLVRA-dependent signaling pathway in modulating the splenic inflammation in response to GMH via the eNOS/NO/TLR4 pathway.

Highlights

Germinal matrix hemorrhage (GMH) is a common neurologic event with high morbidity and mortality in preterm infants
biliverdin reductase-A (BLVRA) treatment attenuated short-term neurological deficits and splenic contraction up to 3 days after GMH Brain morphology was evaluated by Nissl staining on day 3 after GMH
Ventricular volume was significantly increased in the vehicle group compared with sham animals, but BLVRA treatment decreased GMH-induced ventricular dilation (Fig. 1a). 3 days post-GMH, developmental delay was observed in the vehicle group compared with the sham group, as demonstrated in both righting reflex and negative geotaxis

Summary

Introduction

Germinal matrix hemorrhage (GMH) is a common neurologic event with high morbidity and mortality in preterm infants. Spleen has been reported to play a critical role in inflammatory responses by regulating peripheral immune cells which contributes to secondary brain injury. Germinal matrix hemorrhage (GMH) is a common neurological deficit in premature infants and is strongly related to high mortality and morbidity. Spleen is a secondary peripheral immune organ where immune cells were pooled Mounting evidence shows that post-stroke immunological responses are generated from brain, and in the peripheral organs and tissues, including bone marrow, blood, and the spleen. Current studies have investigated splenic responses after stroke and highlighted the effect of the spleen in regulating peripheral immune system which is considerably involved in the secondary brain injury [5]. Splenectomy and irradiation of spleen both successfully attenuate splenic responses induced by brain injury and contribute to decreased brain lesion size and neurodegenerative outcomes [10,11,12]

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