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 ramified morphology with relative small cell bodies and long processes (Figure 1A). They detect injury signals in the CNS and get activated. In the brain they undergo different stages of activation, which can be classified according to the morphological and immune-reactive diversities. In the traumatic brain injury, the phagocytic and amoeboid shape microglial cells (Figure 1B) are of particular interest, since they are considered as the fully activated form of microglia, and are important features for brain tissue destruction and inflammation. Rod microglia were firstly reported by Franz Nissl in 1899, from general paresis patients (Nissl, 1899). They represent a unique cell type of activated microglia with distinct morphology 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). The unique morphology implies they exert specific functions to neuroinflammation; however, this population is largely neglected during the past decades. There 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 conditions, such as traumatic brain injury and stroke, only phagocytic 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 extracellular 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 fluid percussion, rod microglia was observed at the injured cortex 2 days after injury, 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 fibers 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 definition of rod microglia ambiguous and subjective. In that scenarios, researchers characterize microglial phenotype rely on their personal ex-