Program Director/Principal Investigator (Last, First, Middle): Project Summary/Abstract Stroke is a significant neurological illness with few effective treatments. Understanding mechanisms underlying stroke pathophysiology may help identify appropriate treatments. Inflammation following stroke is now recognized to potentiate ischemic injury at least acutely, but may be important in clearing necrotic debris and initiating regenerative processes. Triggering receptor expressed by myeloid cells- 2 (TREM2) is a recently discovered receptor involved in the innate immune system. TREM2 binds to anionic moieties found on bacteria and eukaryotic cells, as well as injured brain cells. TREM2 is also expressed on microglia, where it promotes phagocytosis. We previously found that TREM2 on brain resident microglia is upregulated following brain ischemia, and its deficiency leads to worsened outcome and near complete inhibition of phagocytosis of damaged brain tissue. Further, we discovered that, through the study of bone marrow chimeric mice, TREM2 in brain microglia seem to contribute more to its beneficial functions than TREM2 in circulating myeloid cells (monocytes and macrophages). We also observed that TREM2 is upregulated in bone marrow derived stromal cells (BMSCs) after transplantation in mice exposed to experimental stroke. Recent studies in both the laboratory and clinical trials have focused on the use of BMSCs to improve outcome from stroke, but reasons for this therapeutic effect are not fully clear. Preliminary observations in our lab showed that delivering BMSCs harvested from wildtype mice and implanted in TREM2 deficient mice improved neurological outcome following experimental stroke, and this was associated with upregulation of TREM2 in the transplanted BMSCs. We also noticed that TREM2 deficiency led to increased M1 (pro-inflammatory, detrimental) polarization after experimental stroke compared to inflammatory responses in wildtype mice with intact TREM2.
In Aim 1, we will determine whether a mechanism of BMSC therapy is due to transformation or upregulation of these cells into TREM2 expressing cells, and whether the transfer of TREM2 positive myeloid cells may also improve neurological outcome.
In Aim 2, we will determine whether female mice respond similarly to these interventions.
Aim 3 will then explore how TREM2 may be involved in the beneficial effect of BMSCs and if it is required to polarize microglia and macrophages towards a M2 (anti-inflammatory, beneficial) phenotype. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page
Project Narrative Stroke is a significant neurological illness with few effective treatments. Inflammation following stroke is thought to increase damage due to non specific immune reactions causing injury to adjacent healthy brain tissue. However, inflammation may also be important in removing dead tissue and aiding in recovery. Recent work from our group showed that a recently described receptor, triggering receptor expressed on myeloid cells-2 (TREM2) was important to neurological recovery and the removal of damaged brain tissue, because mice deficient in TREM2 had worse outcome from experimental stroke. We also discovered that bone marrow derived stromal cells (BMSCs) can cause microglia, the brain's resident immune cell, to express TREM2. Further, treating mice lacking TREM2 with BMSCs containing intact TREM2 led to improved outcomes. Since cell based therapies, including BMSCs, are already being studied in stroke patients, this project hopes to develop a better understanding of TREM2 functions in experimental stroke and how BMSC therapy works, and if similar strategies to increase TREM2 might prove to be a useful therapeutic approach. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page