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  1. Author Response

    Reviewer #2 (Public Review):

    This is a single RNA-seq analysis of traumatic brain injury (TBI) in mice that looks at recovery from milder TBI. It addresses an important question of why older individuals may have poor recovery. The investigators undertake unbiased analysis in both young and old mice and identify a number of macrophage, fibroblast, lymphocyte, and more specifically B cell inflammatory programs that are activated and some of which do not recover well in older mice. Taken together, these findings identify unique pathways that could be further investigated in functional studies to examine what immunologic mechanisms in the meninges may drive long-term problems from TBI. The models and analysis are well performed and compelling. This paper can serve as a resource for those who study brain immunology. Open questions include the following: 1) What exactly predisposes to such pro-inflammatory programs in the aged meninges? Epigenetic alterations?, 2) What are the effector mechanisms that negatively impact brain function, and 3) Can bioinformatic approaches reveal putative intercellular communication networks that would lend insight into the spatiotemporal sequence of events and ligand-receptor interactions?

    We are glad to hear that the Reviewer finds our work compelling, well performed and that it will be a good resource for those who wish to study brain immunology. The open questions that the Reviewer brings forth are very compelling areas of future investigation that we believe will help to shape and advance this field in the coming years.

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  2. Evaluation Summary:

    Identification of transcriptional phenotypes driven by TBI across meningeal immune cell subsets and the effect of aging on these responses is an important and not well-defined area in the field. Multiple complementary and high-end approaches are taken to demonstrate the long-lasting effects that TBI drives in the brain and support the main findings of the manuscript. This manuscript will be of interest to readers in the field(s) of neuroimmunology, aging, and traumatic brain injury.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

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  3. Reviewer #1 (Public Review):

    In the current manuscript, Bolte et al., examine how a single TBI alters the heterogeneity of dorsal meningeal immune cell responses and whether age at the time of injury affects long-term transcriptional profiles of this immune compartment of the brain. Multiple complementary approaches were undertaken to achieve high resolution of meningeal transcriptional response(s) to TBI including single-cell sequencing and bulk tissue sequencing. Several innate and adaptive immune phenotypes were quantified at the protein level, demonstrating these disease-associated responses are not solely relegated to transcriptional responses. The majority of the methods and analyses are robust, which is a notable strength of the manuscript. In its current iteration, a weakness is a lack of integration between gene sets that define meningeal immune cell subsets in the single cell data (e.g. Macrophages, Tcells, Bcells, Fibroblasts, etc.) and quantifying these DEGs (up or down-regulated) to examine whether the transcripts are altered in the chronic TBI/aging bulk sequencing data. A more thorough integration of these two datasets and their discussion would significantly bolster the main premise of the manuscript related to the resolution of inflammatory responses to TBI in the young versus the aged condition, chronically.

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  4. Reviewer #2 (Public Review):

    This is a single RNA-seq analysis of traumatic brain injury (TBI) in mice that looks at recovery from milder TBI. It addresses an important question of why older individuals may have poor recovery. The investigators undertake unbiased analysis in both young and old mice and identify a number of macrophage, fibroblast, lymphocyte, and more specifically B cell inflammatory programs that are activated and some of which do not recover well in older mice. Taken together, these findings identify unique pathways that could be further investigated in functional studies to examine what immunologic mechanisms in the meninges may drive long-term problems from TBI. The models and analysis are well performed and compelling. This paper can serve as a resource for those who study brain immunology. Open questions include the following: 1) What exactly predisposes to such pro-inflammatory programs in the aged meninges? Epigenetic alterations?, 2) What are the effector mechanisms that negatively impact brain function, and 3) Can bioinformatic approaches reveal putative intercellular communication networks that would lend insight into the spatiotemporal sequence of events and ligand-receptor interactions?

    Was this evaluation helpful?