Reciprocal Interaction Between Pericytes and Macrophage in Poststroke Tissue Repair and Functional Recovery

Abstract

Background and Purpose: Poststroke tissue repair, comprised of macrophage-mediated clearance of myelin debris and pericyte-mediated fibrotic response within the infarct area, is an important process for functional recovery. Herein, we investigated the reciprocal interaction between pericytes and macrophages during poststroke repair and functional recovery. Methods: We performed a permanent middle cerebral artery occlusion in both wild-type and pericyte-deficient PDGFRβ (platelet-derived growth factor receptor β) heterozygous knockout ( Pdgfrb +/− ) mice and compared histological changes and neurological functions between the 2 groups. We also examined the effects of conditioned medium harvested from cultured pericytes, or bone marrow-derived macrophages, on the functions of other cell types. Results: Localization of PDGFRβ-positive pericytes and F4/80-positive macrophages was temporally and spatially very similar following permanent middle cerebral artery occlusion. Intrainfarct accumulation of macrophages was significantly attenuated in Pdgfrb +/− mice. Intrainfarct pericytes expressed CCL2 (C-C motif ligand 2) and CSF1 (colony stimulating factor 1), both of which were significantly lower in Pdgfrb +/− mice. Cultured pericytes expressed Ccl2 and Csf1 , both of which were significantly increased by PDGF-BB and suppressed by a PDGFRβ inhibitor. Pericyte conditioned medium significantly enhanced migration and proliferation of bone marrow-derived macrophages. Poststroke clearance of myelin debris was significantly attenuated in Pdgfrb +/− mice. Pericyte conditioned medium promoted phagocytic activity in bone marrow-derived macrophages, also enhancing both STAT3 (signal transducer and activator of transcription 3) phosphorylation and expression of scavenger receptors, Msr1 and Lrp1 . Macrophages processing myelin debris produced trophic factors, enhancing PDGFRβ signaling in pericytes leading to the production of ECM (extracellular matrix) proteins and oligodendrogenesis. Functional recovery was significantly attenuated in Pdgfrb +/− mice, parallel with the extent of tissue repair. Conclusions: A reciprocal interaction between pericytes and macrophages is important for poststroke tissue repair and functional recovery.

Effect of Pericytes on Cerebral Microvasculature at Different Time Points of Stroke

“…The study quality scores ranged from 3 to 7, with a total score of 10. One study scored 3 [ 19 ]; 8 studies scored 4 [ 7 , 16 – 18 , 20 , 26 , 29 , 34 ]; the quantities of studies scoring 5 [ 15 , 25 , 27 , 28 , 31 , 35 ] and 6 [ 21 – 24 , 30 , 33 ] are both 6; one [ 32 ] study scored 7. All included studies were peer-reviewed publications, and all animals were randomized.…”

Efferocytosis Mediated Modulation of Injury after Neonatal Brain Hypoxia-Ischemia

“…Peripheral blood macrophages are involved in efferocytosis upon the insult [ 81 ], but it is unclear whether they participate in the maintenance of brain homeostasis also under normal conditions. The “non-professional” efferocytes include oligodendrocytes [ 4 , 32 , 97 ], astrocytes [ 98 ], endothelial cells [ 99 , 100 ], pericytes [ 101 , 102 ] in the brain or Schwann cells in the peripheral nervous system [ 103 ], etc. The “non-professional” efferocytes substantially contribute to brain efferocytosis, as well.…”

“…Pericytes indirectly recruit macrophages to the injury site and promote phagocytic activity in macrophages. The macrophages process myelin debris and produce trophic factors, enhancing PDGFRβ signaling in pericytes leading to the production of extracellular matrix proteins and oligodendrogenesis [ 102 ]. Thus, the process of efferocytosis of dying neurons after a stroke is characterized by active communication among multiple cells taking over specific functions.…”

The Impact of Inflammatory Immune Reactions of the Vascular Niche on Organ Fibrosis

“…Macrophages living in the vascular niche are also regulated by ECs and pericytes. ECs and pericytes promote the recruitment and maturation of macrophages in the vascular niche by secreting various chemokines and cytokines (such as the transcription factor Nr4a1 (Nur77), intracellular adhesion molecule-1 (Icam-1)) and macrophages can also secrete VEGFA to promote endothelial proliferation (Frangogiannis, 2019;Hernandez and Iruela-Arispe, 2020;Shibahara et al, 2020).…”