Acute inflammatory profiles differ with sex and age after spinal cord injury

Abstract

Background Sex and age are emerging as influential variables that affect spinal cord injury (SCI) recovery. Despite a changing demographic towards older age at the time of SCI, the effects of sex or age on inflammation remain to be elucidated. This study determined the sex- and age-dependency of the innate immune response acutely after SCI. Methods Male and female mice of ages 4- and 14-month-old received T9 contusion SCI and the proportion of microglia, monocyte-derived macrophages (MDM), and neutrophils surrounding the lesion were determined at 3- and 7-day post-injury (DPI) using flow cytometry. Cell counts of microglia and MDMs were obtained using immunohistochemistry to verify flow cytometry results at 3-DPI. Microglia and MDMs were separately isolated using fluorescence-activated cell sorting (FACS) at 3-day post-injury (DPI) to assess RNA expression of 27 genes associated with activation, redox, and debris metabolism/clearance. Results Flow cytometry revealed that being female and older at the time of injury significantly increased MDMs relative to other phagocytes, specifically increasing the ratio of MDMs to microglia at 3-DPI. Cell counts using immunohistochemistry revealed that male mice have more total microglia within SCI lesions that can account for a lower MDM/microglia ratio. With NanoString analyses of 27 genes, only 1 was differentially expressed between sexes in MDMs; specifically, complement protein C1qa was increased in males. No genes were affected by age in MDMs. Only 2 genes were differentially regulated in microglia between sexes after controlling for false discovery rate, specifically CYBB (NOX2) as a reactive oxygen species (ROS)-associated marker as well as MRC1 (CD206), a gene associated with reparative phenotypes. Both genes were increased in female microglia. No microglial genes were differentially regulated between ages. Differences between microglia and MDMs were found in 26 of 27 genes analyzed, all expressed higher in MDMs with three exceptions. Specifically, C1qa, cPLA2, and CD86 were expressed higher in microglia. Conclusions These findings indicate that inflammatory responses to SCI are sex-dependent at both the level of cellular recruitment and gene expression.

The Inflammatory Response after Moderate Contusion Spinal Cord Injury: A Time Study

“…A recent study by Stewart et al [ 83 ] supported the inflammation after SCI is sex-dependent both at the level of cellular recruitment and phenotype, effects of aging, however, while present, were overall less pronounced. Interestingly though, Tnf expression was one of the genes that differed between 4-month-old and 14-month-old SCI mice, whereas sex did not appear to affect Tnf expression [ 83 ]. How the temporal and cellular expression of TNF changes with age and sex after SCI remains to be elucidated.…”

“…A limitation of the present study is that only female mice were used. The acute inflammatory profile has been demonstrated to differ between female and male mice [ 83 , 84 ]. Additionally, the inhibition of TNF-TNFR1 signaling has been demonstrated to be therapeutic for neuropathic pain in males but not in females [ 85 ], highlighting the importance of incorporating both male and female groups in future SCI research to account for sexual dimorphisms.…”

Delayed administration of nafamostat mesylate inhibits thrombin-mediated blood–spinal cord barrier breakdown during acute spinal cord injury in rats

“…According to epidemiology of traumatic SCI either in US or in China, the incidence rate in males is four or five times higher than female [ 57 , 58 ], and there is a difference in the recovery between sex in both rat models and human beings in clinic [ 59 ]. There is emerging evidence that sex and age are important variables that affect SCI recovery, including on the acute inflammatory response [ 60 ]. Therefore, to further push the translation of nafamostat on SCI, more preclinical experiments should be conducted.…”

Photobiomodulation inhibits the activation of neurotoxic microglia and astrocytes by inhibiting Lcn2/JAK2-STAT3 crosstalk after spinal cord injury in male rats

“…Although more than 80% of patients are men aged approximately 30 years old [ 65 ], some reports have shown that female rodents may have better outcomes than male rodents after SCI [ 66 , 67 ]. A recent study showed stronger total inflammation and more microglia at the lesion epicenter in SCI male rats than in SCI female rats, while the number of macrophages in the damaged area was higher in SCI female rats [ 68 ]. Considering that PBM in our study inhibited the activation of total Iba1 + cells indiscriminately, we predict that the therapeutic effects of PBM can be reproduced in female rat models of SCI without changing the overall conclusions, although this requires confirmation in the future.…”