Few stroke laboratories study female animals or use cell models of ischemic brain injury that are sex-specific. In part, this is due to the historical assumption that cellular/molecular injury and repair mechanisms are the same in males vs. females. The persistent lack of pre-clinical animal data in both sexes poses a severe evidence gap for clinical trialists who will test new therapies in women and men. In this application, we test the overarching hypothesis that the evolution of post-ischemic inflammatory cycling between the brain and peripheral immune system is strongly influenced by biological sex, including sexually dimorphic immune cell subsets and key inflammatory mechanisms that affect brain-spleen-brain cycling of inflammatory cells after focal cerebral ischemia.
Aim 1 will test the hypotheses that evolving cerebral ischemic injury elicits splenic damage in tandem with brain microvascular and parenchymal inflammation that is more profound and is mediated by different immunocyte populations (monocytes vs. T lymphocytes) in males vs. females.
Aim 2 determines if T lymphocyte-mediated injury in post-ischemic brain is greater in females due to lower levels of peroxisome proliferator activated receptor alpha (PPAR?) in T lymphocytes. These hypotheses predict that (a) while splenectomy benefits the injured brain of both sexes by eliminating immunocytes nurtured within the spleen, adoptive transfer of female vs. male T lymphocytes sensitized to focal cerebral ischemia into splenectomized same sex recipients selectively increases female cerebral damage more so than males following MCAO and that (b) female vulnerability to T lymphocyte-mediated injury is due in part to a lack of protective PPAR? signaling mechanisms.
Aim 3 will evaluate whether monocyte trafficking from spleen to post- ischemic brain is sex-specific. The hypotheses are that (a) males exhibit an early and more robust recruitment of CD45highCD11b+ macrophages and CD11c+ dendritic cells into post-ischemic brain relative to females;(b) this recruitment is due in part to higher matrix metalloproteinase (MMP)-9 expression in male monocytes, thus facilitating their transmigration;(c) male mice deficient in CD11b+ (macrophage """"""""knockout"""""""") or in CD11c+ myeloid cells (dendritic cell """"""""knockout"""""""") will more greatly benefit by loss of these cells than will females following focal cerebral ischemia. Findings from this application could therefore lead to the development of new therapies for stroke such as PPAR? agonists for females and MMP-9 antagonists for males.

Public Health Relevance

Ischemic stroke is a leading cause of death and disability in the United States, yet relatively little is known about the contribution to and effects on the immune system during stroke. The application focuses on early and late events in the peripheral immune system during stroke and important changes in the spleen that occur simultaneously with the evolving brain injury. We have preliminary evidence that this process is not identical in both males and females and are studying the relevant sex differences.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS076013-02
Application #
8420420
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
2012-04-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$466,719
Indirect Cost
$163,655
Name
Oregon Health and Science University
Department
Neurology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Dotson, Abby L; Wang, Jianming; Liang, Jian et al. (2016) Loss of PPARα perpetuates sex differences in stroke reflected by peripheral immune mechanisms. Metab Brain Dis 31:683-92
Yang, Liu; Kong, Ying; Ren, Honglei et al. (2016) Upregulation of CD74 and its potential association with disease severity in subjects with ischemic stroke. Neurochem Int :
Dotson, Abby L; Wang, Jianming; Chen, Yingxin et al. (2016) Sex differences and the role of PPAR alpha in experimental stroke. Metab Brain Dis 31:539-47
Wang, Jianyi; Ye, Qing; Xu, Jing et al. (2016) DRα1-MOG-35-55 Reduces Permanent Ischemic Brain Injury. Transl Stroke Res :
Zhu, Wenbin; Casper, Amanda; Libal, Nicole L et al. (2015) Preclinical evaluation of recombinant T cell receptor ligand RTL1000 as a therapeutic agent in ischemic stroke. Transl Stroke Res 6:60-8
Pennypacker, Keith R; Offner, Halina (2015) The role of the spleen in ischemic stroke. J Cereb Blood Flow Metab 35:186-7
Zhu, W; Dotson, A L; Libal, N L et al. (2015) Recombinant T-cell receptor ligand RTL1000 limits inflammation and decreases infarct size after experimental ischemic stroke in middle-aged mice. Neuroscience 288:112-9
Wang, Jianming; Dotson, Abby L; Murphy, Stephanie J et al. (2015) Adoptive transfer of immune subsets prior to MCAO does not exacerbate stroke outcome in splenectomized mice. J Syst Integr Neurosci 1:20-28
Dotson, Abby L; Wang, Jianming; Saugstad, Julie et al. (2015) Splenectomy reduces infarct volume and neuroinflammation in male but not female mice in experimental stroke. J Neuroimmunol 278:289-98
Offner, Halina (2014) Modeling immunity and inflammation in stroke: don't be afraid of mice? Stroke 45:e181-2

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