A revisit of rod microglia in preclinical studies

A revisit of rod microglia in preclinical studies

Microglial cells (or microglia) are the mononuclear phagocytes residing in the central nervous system (CNS). In homeostasis, they showed rami fi ed morphology with relative small cell bod‐ies and long processes (Figure 1A).ey detect injury signals in the CNS and get activated. In the brain they undergo di ff erent stages of activation, which can be classified according to the morphological and immune‐reactive diversities. In the traumat‐ic brain injury, the phagocytic and amoeboid shape microglial cells (Figure 1B) are of particular interest, since they are con‐sidered as the fully activated form of microglia, and are import‐ant features for brain tissue destruction and in fl ammation.

Rod microglia were fi rstly reported by Franz Nissl in 1899, from general paresis patients (Nissl, 1899). They represent a unique cell type of activated microglia with distinct morphol‐ogy from amoeboid microglia. They exhibit a rod‐like cell body without polarized processes. Usually, the rod microglia get aligned one another along their elongated axis (Figure 1C) (Taylor et al., 2014).e unique morphology implies they exert specific functions to neuroinflammation; however, this population is largely neglected during the past decades.ere are occasional reports of rod microglia in different types of neuropathies, such as viral‐encephalitis, lead encephalopathy, and slowly progressed hippocampal ischemia (Graeber and Mehraein, 1994). It has been suggested that the morphological integrity of tissue microstructure was one pre‐requisite for the rod phenotype; while in rapidly progressed neurological con‐ditions, such as traumatic brain injury and stroke, only phago‐cytic and amoeboid shape microglial cells were found. In fact, recent studies demonstrated the existence of rod microglia in postmortem brain samples from patients with Alzheimer’s disease and other neurodegenerative disorders (Odawara et al., 1995). Notably, rod microglia expressed high level of MHC class II beta‐chain (Graeber and Mehraein, 1994), which might be important in maintaining their morphology within the ex‐tracellular matrix.

In past decade, several animal studies revisited the potential functions of rod microglia in the nervous system. For instance, in experimental brain injury induced by fl uid percussion, rod microglia was observed at the injured cortex 2 days aer inju‐ry, expressing markers of activated microglia, including CD68 and OX‐6 (Ziebell et al., 2012). It is found that rod microglia became bipolarized and attached to neuronal processes or nerve fi bers to form trains (Figure 1C) (Taylor et al., 2014). It is also observed that rod microglia seem to get aligned with each other; however, the potential interaction (e.g., gap junctions) between different rod microglia remains elusive. Notably, the unique morphology and alignment make the de fi nition of rod microglia ambiguous and subjective. In that scenarios, research‐ers characterize microglial phenotype rely on their personal ex‐periences, which are subjective and time consuming. In a recent study, the researchers utilized customized computer soware to quantitatively analyze the morphology (e.g., orientation angles) (Zhang et al., 2016). This thus provides descriptive definition makes rod microglial phenotype unambiguous and objective. Moreover, the automatic process allows high throughput analy‐sis with precise details.

Figure 1e diverse morphologies of microglia in the central nervous system (CNS).

In a di ff erent set of studies, rod microglia have been reported in the retina undergoing retinal ganglion cell (RGC) loss in rat glaucoma models, a type of chronic ocular degeneration associ‐ated with optic neuropathy (Rojas et al., 2014).e retinal rod microglia have been found to be restricted in the nerve fiber layer (NFL)/ganglion cell layer (GCL), with a close relationship to RGC axon bundles. Therefore, they were radially aligned pointing to the optic nerve head (ONH) (Figure 1C). It has also been found that retinal rod microglial cells are likely to express M1‐ or M2‐like microglial markers, which are actually ex‐pressed by amoeboid morphology microglial cells. Interestingly, in another study with acute ocular injury model, retinal rod microglial cells were observed 3 days aer optic nerve transec‐tion, peaked at 3 weeks and disappeared aer 6 weeks following the injury (Yuan et al., 2015). These rod microglial cells were phagocytic, and acted as the majority of activated microglial cells in the injured retina.e study further showed that the rod microglia cells are actually proliferating, especially in the period of 3 days to 2 weeks aer injury. In contrast, in fi ltrating microg‐lia di ff erentiated from the myeloid precursor cells in the blood only have a minimal contribution (Yuan et al., 2015). In another study of glaucoma model by the acute elevation of intra‐ocular pressure, activated microglia in the NFL/GCL also exhibited the rod phenotype, though the authors did not use this terminology (Wang et al., 2014). In this study, inhibition of rod microglia by minocycline signi fi cantly ameliorated the RGC loss. Collective‐ly, these results suggested that rod microglia might be a com‐mon neuropathological feature in RGC insults of the retina, and worth more attention.

It has been believed that the rod morphology microglia might represent a mild level of neural injury and relative in‐tegrity of the surrounding tissues. In fact,in vitrocultured rod microglia exhibited low levels of M1‐/M2‐like microglial markers, and showed cell proliferation. With LPS challenge, they were further activated, became amoeboid shape and ex‐press pro‐in fl ammatory M1‐like markers (Tam and Ma, 2014). Therefore, the appearance of rod microglia in neural tissues could indicate a mild progression of the injury signaling; the use of rod‐to‐amoeboid microglia ratio therefore might be of interest to pathological analyses in clinical trials, especially in neurodegenerative diseases.

In summary, rod microglia represent a unique kind of ac‐tivated microglial cells during neurodegenerative disorders. They get aligned along with axonal fibers in the brain and retina.ey originate from resident microglial proliferation in responding to neural insults and exert phagocytic functions.ey usually appear in mild neurodegeneration.

Yanxia Rao, Yu-Xiang Liang, Bo Peng＊

Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong Province, China (Peng B) School of Biomedical Sciences, Li Ka Shing Faculty of Medicine,e University of Hong Kong, Hong Kong Special Administrative Region, China (Rao Y) State Key Laboratory of Brain and Cognitive Sciences,e University of Hong Kong, Hong Kong Special Administrative Region, China (Liang YX)

＊Correspondence to: Bo Peng, Ph.D., bopeng@connect.hku.hk.

Accepted:2016-11-28

orcid: 0000-0003-4183-5939 (Bo Peng)

Graeber MB, Mehraein P (1994) Microglial rod cells. Neuropathol Appl Neu‐robiol 20:178‐180.

Nissl F (1899) Ueber einige Beziehungen zwischen Nervenzellerkrankungen und gliosen Erscheinungen bei verschiedenen Psychosen. Arch Psychiatr 32:656‐676.

Odawara T, Iseki E, Kosaka K, Akiyama H, Ikeda K, Yamamoto T (1995) In‐vestigation of tau‐2 positive microglia‐like cells in the subcortical nuclei of human neurodegenerative disorders. Neurosci Lett 192:145‐148.

Rojas B, Gallego BI, Ramirez AI, Salazar JJ, de Hoz R, Valiente‐Soriano FJ, Aviles‐Trigueros M, Villegas‐Perez MP, Vidal‐Sanz M, Trivino A, Ramirez JM (2014) Microglia in mouse retina contralateral to experimental glauco‐ma exhibit multiple signs of activation in all retinal layers. J Neuroin fl am‐mation 11:133.

Tam WY, Ma CH (2014) Bipolar/rod‐shaped microglia are proliferating mi‐croglia with distinct M1/M2 phenotypes. Sci Rep 4:7279.

Taylor SE, Morganti‐Kossmann C, Lifshitz J, Ziebell JM (2014) Rod microg‐lia: a morphological de fi nition. PLoS One 9:e97096.

Wang K, Peng B, Lin B (2014) Fractalkine receptor regulates microglial neu‐rotoxicity in an experimental mouse glaucoma model. Glia 62:1943‐1954.

Yuan TF, Liang YX, Peng B, Lin B, So KF (2015) Local proliferation is the main source of rod microglia aer optic nerve transection. Sci Rep 5:10788.

Zhang Y, Peng B, Wang S, Liang YX, Yang J, So KF, Yuan TF (2016) Image processing methods to elucidate spatial characteristics of retinal microglia aer optic nerve transection. Sci Rep 6:21816.

Ziebell JM, Taylor SE, Cao T, Harrison JL, Lifshitz J (2012) Rod microglia: elongation, alignment, and coupling to form trains across the somatosen‐sory cortex aer experimental di ff use brain injury. J Neuroin fl ammation 9:247.

10.4103/1673-5374.195276

How to cite this article:Rao Y, Liang YX, Peng B (2017) A revisit of rod microglia in preclinical studies. Neural Regen Res 12(1):56-57.

Open access statement:is is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.