M-CSF, IL-6, and TGF-β promote generation of a new subset of tissue repair macrophage for traumatic brain injury recovery

Abstract

Traumatic brain injury (TBI) leads to high mortality rate. We aimed to identify the key cytokines favoring TBI repair and found that patients with TBI with a better outcome robustly increased concentrations of macrophage colony-stimulating factor, interleukin-6, and transforming growth factor–β (termed M6T) in cerebrospinal fluid or plasma. Using TBI mice, we identified that M2-like macrophage, microglia, and endothelial cell were major sources to produce M6T. Together with the in vivo tracking of mCherry+ macrophages in zebrafish models, we confirmed that M6T treatment accelerated blood-borne macrophage infiltration and polarization toward a subset of tissue repair macrophages that expressed similar genes as microglia for neuroprotection, angiogenesis and cell migration. M6T therapy in TBI mice and zebrafish improved neurological function while blocking M6T-exacerbated brain injury. Considering low concentrations of M6T in some patients with poor prognostic, M6T treatment might repair TBI via generating a previously unidentified subset of tissue repair macrophages.

Spatiotemporal transcriptome at single-cell resolution reveals key radial glial cell population in axolotl telencephalon development and regeneration

“…Strikingly, the number of REARGCs appeared to be significantly increased in the VZ along the medium and lateral pallium region and eventually covered the whole wound area around 20 DPI, and disappeared after 30 DPI (Figure 3B, Figure S13D and Figure S16-S22). Unlike brain wound healing process in mammals, during which microglias and macrophages are the first line of cell types responsible for injury site filling (Li et al, 2021b), REARGCs appeared to be the dominant cell type in the wound area between 2 and 20 DPI, suggesting they may be involved in multiple aspects of tissue regeneration process (Figure 3A-B).…”

The Promoting Effect of Traumatic Brain Injury on the Incidence and Progression of Glioma: A Review of Clinical and Experimental Research

“…In normal conditions, the expression of IL-6 is very low, whereas, during traumatic brain injury, its production increases considerably. 48 Brain injury elevates IL-6 production in both serum and CSF to high concentration. Notably, multiple TBI patients’ samples have also showed that the combination of elevated IL-6 concentrations is correlated with better outcomes in patients with TBI, suggesting IL-6 as a new therapeutic strategy as well as for prediction of disease outcome of patients with TBI.…”

“…Notably, multiple TBI patients’ samples have also showed that the combination of elevated IL-6 concentrations is correlated with better outcomes in patients with TBI, suggesting IL-6 as a new therapeutic strategy as well as for prediction of disease outcome of patients with TBI. 49 Importantly, high levels of IL-6 in the brain generally result in an adverse impact on microcirculation and lead to the destruction of the blood-brain barrier in an obviously wider area compared to the initial area of trauma. 27 Thus, in traumatic brain injuries, it is crucial that the blood-brain barrier is not initially compromised, as IL-6 can subsequently promote the entry of macrophages to the site of injury and aggravate brain edema.…”

Glucocorticoids as Regulators of Macrophage-Mediated Tissue Homeostasis

“…M1 macrophages are mainly involved in pro-inflammatory responses, classically generated upon induction by microbial products, such as LPS and pectidoglycan and pro-inflammatory cytokines such as interferon-gamma. M2 macrophages are mainly involved in anti-inflammatory responses, ultimately associated with promoting wound healing, tissue repair and for resolving inflammation (31,32). Glucocorticoids have been related to a M2like phenotype, where the capacity to promote tissue repair and wound healing has been demonstrated (33)(34)(35).…”