Involvement of Progranulin and Granulin Expression in Inflammatory Responses after Cerebral Ischemia.

Ichiro Horinokita,Tatsuaki Yamaguchi,Bo Yuan,Norio Takagi,Risa Mizumura,Hideki Hayashi,Akane Usui,Rika Oteki

doi:10.3390/ijms20205210

Abstract

Progranulin (PGRN) plays a crucial role in diverse biological processes, including cell proliferation and embryonic development. PGRN can be cleaved by neutrophil elastase to release granulin (GRN). PGRN has been found to inhibit inflammation. Whereas, GRN plays a role as a pro-inflammatory factor. However, the pathophysiological roles of PGRN and GRN, at early stages after cerebral ischemia, have not yet been fully understood. The aim of this study was to obtain further insight into the pathologic roles of PGRN and GRN. We demonstrated that the amount of PGRN was significantly increased in microglial cells after cerebral ischemia in rats and that neutrophil elastase activity was also increased at an early stage after cerebral ischemia, resulting in the production of GRN. The inhibition of neutrophil elastase activity suppressed PGRN cleavage and GRN production, as well as the increase in pro-inflammatory cytokines, after cerebral ischemia. The administration of an elastase inhibitor decreased the number of injured cells and improved the neurological deficits test scores. Our findings suggest that an increase in the activity of elastase to cleave PGRN, and to produce GRN, was involved in an inflammatory response at the early stages after cerebral ischemia, and that inhibition of elastase activity could suppress the progression of cerebral ischemic injury.

Highlights

Ischemic stroke continues to be a leading cause of disability and mortality worldwide
Glial fibrillary acidic protein (GFAP)-positive astrocytes in sham-operated animals did not express PGRN, PGRN was detected in MAP2-positive neuron
Iba-1-positive microglia were dispersed with a ramified form in the sham-operated rats, whereas round and ameboid-like microglia expressing PGRN were evident after microsphere-induced cerebral embolism (ME) (Figure 1B)

Summary

Introduction

Ischemic stroke continues to be a leading cause of disability and mortality worldwide. The clinical benefits of t-PA treatment manifest when it is administered within 4.5 h of stroke onset, delayed treatment with t-PA leads to severe complications. This is a result of increased risk of hemorrhagic complications, a breakdown of the blood-brain barrier (BBB), and the neurotoxic effects of t-PA [1,2]. It has been shown that macrophages and neutrophils, infiltrating through an injured-BBB, contribute to the release of inflammatory cytokines in the brain parenchyma. Controlling inflammation-related factors in the infarct area and its surrounding area can be a link to the development of new therapeutic strategies against ischemic stroke

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