Abstract
Sex is a key biological variable in traumatic brain injury (TBI) and plays a significant role in neuroinflammatory responses. However, the molecular mechanisms contributing to this sexually dimorphic neuroinflammatory response remain elusive. Here we describe a significant and previously unreported tissue enrichment and sex-specific alteration of a set of inflammatory microRNAs (miRNAs) in CD11b+ cells of brain and bone marrow isolated from naïve mice as well as mice subjected to TBI. Our data from naïve mice demonstrated that expression levels of miR-146a-5p and miR-150-5p were relatively higher in brain CD11b+ cells, and that miR-155-5p and miR-223-3p were highly enriched in bone marrow CD11b+ cells. Furthermore, while miR-150-5p and miR-155-5p levels were higher in male brain CD11b+ cells, no significant sexual difference was observed for miR-146a-5p and miR-223-3p. However, TBI resulted in sex-specific differential responses of these miRNAs in brain CD11b+ cells. Specifically, miR-223-3p levels in brain CD11b+ cells were markedly elevated in both sexes in response to TBI at 3 and 24h, with levels in females being significantly higher than males at 24h. We then focused on analyzing several miR-223-3p targets and inflammation-related marker genes following injury. Corresponding to the greater elevation of miR-223-3p in females, the miR-223-3p targets, TRAF6 and FBXW7 were significantly reduced in females compared to males. Interestingly, anti-inflammatory genes ARG1 and IL4 were higher in females after TBI than in males. These observations suggest miR-223-3p and other inflammatory responsive miRNAs may play a key role in sex-specific neuroinflammatory response following TBI.
Highlights
Neuroinflammation is recognized as a critical factor to acute and chronic secondary injury following traumatic brain injury (TBI)
While miR-146a and miR-150 levels were detected in bone marrow CD11b + cells in both females and males, they were more than 25-fold higher in brain CD11b + cells compared to bone marrow in both sexes (Fig. 1)
The inflammatory miRNAs examined in this study play key roles in inflammatory signaling in myeloid cells and are all implicated in TBI (Liu et al 2014; Redell et al 2009; Wang et al 2015): miR-146a is a negative regulator of NF-κB pathway (Taganov et al 2006); miR-223-3p plays a key role in limiting myeloid cell pro-inflammatory signaling (Jiao et al 2021); miR-155-5p is a highly inducible, proinflammatory miRNA (Jablonski et al 2016; Sun et al 2012); and miR-150-5p is an important modulator for differentiation and activation of immune cells (Zhou et al 2007)
Summary
Neuroinflammation is recognized as a critical factor to acute and chronic secondary injury following traumatic brain injury (TBI). While the acute inflammatory stage is essential for removal of cellular debris and promoting cellular repair, dysregulation of this response leads to chronic microglia activation and pro-inflammatory signaling impacting long-term neurological function (Johnson et al 2013; Loane et al 2014; Pierce et al 1998) This is characterized by the excessive release of pro-inflammatory factors by resident and recruited myeloid cells that differentiate along a continuum from cytotoxic to reparative phenotypes (Jin et al 2012; Kumar et al 2016; Morganti et al 2016). No studies have revealed the involvement of these miRNAs to sex-specific neuroinflammatory responses
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