Microglial CD11b Knockout Contributes to Axonal Debris Clearance and Axonal Degradation Attenuation via IGF-1 After Acute Optic Nerve Injury

Abstract

Purpose Microglial clearance of axonal debris is an essential response for management of traumatic optic neuropathy. Inadequate removal of axonal debris leads to increased inflammation and axonal degeneration after traumatic optic neuropathy. The present study investigated the role of CD11b (Itgam) in axonal debris clearance and axonal degeneration. Methods Western blot and immunofluorescence were used to detect CD11b expression in the mouse optic nerve crush (ONC) model. Bioinformatics analysis predicted the possible role of CD11b. Cholera toxin subunit B (CTB) and zymosan were used to assay phagocytosis by microglia in vivo and in vitro, respectively. CTB was also used to label functionally intact axons after ONC. Results CD11b is abundantly expressed after ONC and participates in phagocytosis. Microglia from Itgam −/− mice exhibited more significant phagocytosis of axonal debris than wild-type microglia. In vitro experiments confirmed that the CD11b gene defect in M2 microglia leads to increased insulin-like growth factor-1 secretion and thus promotes phagocytosis. Lastly, following ONC, Itgam −/− mice exhibited elevated expression of neurofilament heavy peptide and Tuj1, along with more intact CTB-labeled axons when compared with wild-type mice. Moreover, the inhibition of insulin-like growth factor-1 decreased CTB labeling in Itgam −/− mice after injury. Conclusions CD11b limits microglial phagocytosis of axonal debris in traumatic optic neuropathy, as demonstrated by increased phagocytosis with CD11b knockout. The inhibition of CD11b activity may be a novel approach to promote central nerve repair.

Effect of astrocyte GPER on the optic nerve inflammatory response following optic nerve injury in mice

“…Mice were anesthetized via intraperitoneal injection of 1 % sodium pentobarbital, according to the classical ONC model procedure [ 2 , 20 ]. The exposed left optic nerve was crushed 1.5 mm behind the left eyeball for 10 s using ultrafine autoclamps, without damaging the retinal vessels or disturbing the blood supply.…”

“…Traumatic optic neuropathy (TON) is a pathology resulting from direct or indirect optic nerve crush (ONC), which is associated with a substantial loss of retinal ganglion cells (RGCs) and their axons [ 1 , 2 ]. This loss of RGCs and axonal degeneration can cause partial or permanent visual impairment following injury.…”