Brain endothelial CXCL12 attracts protective Natural Killer cells during ischemic stroke

Abstract

Innate lymphoid cells (ILCs) have a function in homeostasis and immune responses, but their role in ischemic brain insult is unknown. Here, we report that ILCs are not resident within the brain parenchyma during steady-state conditions, but are attracted after ischemic stroke. Specifically, we identified NK cells, ILC1s, ILC2s and ILC3s within the lesion, the highest influx being observed for NK cells and ILC1s. We further show that Cxcl12 expressed at the blood-brain barrier is essential for NK cells and NKp46+ ILC3s to migrate toward the lesion. Complementary, Cxcr4-deficiency in NK cells prevented NK cells from entering the infarct area. The lack of NK cell migration resulted in a higher neurological deficit in the beam-walk sensorimotor test. Our data show a new role for blood-brain barrier-derived Cxcl12 in attracting protective NK cells to ischemic brain lesions and identifies a new Cxcl12/ Cxcr4-mediated component of the innate immune response to stroke.

Innate Lymphoid Cells in the Central Nervous System

“…Whether the CD49a + CD49b + Eomes − intILC1s are unique meningeal resident cells and are functionally different remains unknown. Both NKs and ILC1s have been observed within the meninges during steady-state conditions ( 3 , 38 , 42 , 43 ) ( Figure 1 ). Moreover, these two populations recirculate through peripheral lymphoid tissues ( 35 ), raising the question whether NKs and ILC1s within the meninges are migratory or resident.…”

“…Innate and adaptive immune cells including microglia, neutrophils, monocytes and lymphocytes play multiphasic roles in ischemic stroke and impact the pathogenesis of ischemic brain injury ( 70 – 73 ). NK cells have been detected in the brain parenchyma of stroke patients and mouse models with induced ischemic stroke ( 43 , 74 , 75 ). We observed that the robust accumulation of NK cells in the stroke lesion is caused by progressive migration rather than in situ proliferation ( 43 ).…”

“…NK cells have been detected in the brain parenchyma of stroke patients and mouse models with induced ischemic stroke ( 43 , 74 , 75 ). We observed that the robust accumulation of NK cells in the stroke lesion is caused by progressive migration rather than in situ proliferation ( 43 ). The main chemotaxis described thus far for controlling migration of NKs towards the lesion are the CX3CL1/CX3CR1 and CXCL12/CXCR4 axis ( 43 , 74 ).…”

“…We observed that the robust accumulation of NK cells in the stroke lesion is caused by progressive migration rather than in situ proliferation ( 43 ). The main chemotaxis described thus far for controlling migration of NKs towards the lesion are the CX3CL1/CX3CR1 and CXCL12/CXCR4 axis ( 43 , 74 ). The roles for NK cells in ischemic stroke are contradictionary.…”

“…However, it has been shown that there are no NK1.1 + (ex)ILC3 within the CNS by using the RORc GFP fate mapping reporter mouse model ( 38 ). Moreover, the presence of the RORγt + ILC population is very limited in ischemic stroke brain when compared to the NK cells and ILC1 ( 43 ). Therefore, studies using anti-NK1.1 to mediate depletion affect most likely only NKs and ILC1s, but not ILC3s within the CNS.…”