Progesterone protects endothelial cells after cerebrovascular occlusion by decreasing MCP-1- and CXCL1-mediated macrophage infiltration

Abstract

The neuroprotective effects of progesterone after ischemic stroke have been established, but the role of progesterone in promoting cerebrovascular repair remains under-explored. Male Sprague–Dawley rats underwent transient middle cerebral artery occlusion (tMCAO) for 90 min followed by reperfusion for 3 days. Progesterone (8 mg/kg/day) was administered intraperitoneally at 1 hour after initial occlusion followed by subcutaneous injections at 6, 24 and 48 hours post-occlusion. Rats were euthanized after 72 hours and brain endothelial cell density and macrophage infiltration were evaluated within the cerebral cortex. We also assessed progesterone’s ability to induce macrophage migration towards hypoxic/reoxygenated cultured endothelial cells. We found that progesterone treatment post-tMCAO protects ischemic endothelial cells from macrophage infiltration. We further demonstrate that infiltration of monocytes/macrophages can be induced by potent chemotactic factors such as monocyte chemoattractant protein-1 (MCP-1) and the chemokine ligand 1 (CXCL1), secreted by hypoxic/reoxygenated endothelial cells. Progesterone blunts secretion of MCP-1 and CXCL1 from endothelial cells after hypoxia/reoxygenation injury and decreases leukocyte infiltration. The treatment protects ischemic endothelial cells from macrophage infiltration and thus preserves vascularization after ischemic injury.

CTLA4 blockade reduces immature myeloid cells in head and neck squamous cell carcinoma

“…CXCL1 was reported to promote macrophage infiltration in addition to its recruitment of MDSCs. 42 This finding coincides with the current result that M2 macrophages were recruited to the site of tumor in our mouse model.…”

Parity History Determines a Systemic Inflammatory Response to Spread of Ovarian Cancer in Naturally Aged Mice

“…In agreement with our results, parity significantly reduced omental monocyte subsets and B1-B lymphocytes in the MOSE model at middle age, with concomitant decreased expression of various chemokines and polarization factors including CCL2 [ 46 ]. In other tissue contexts, recent reports indicate that progestin suppressed TNF-α induced proliferation and CCL2 secretion of endometrial stromal cells in vitro [ 47 ], while P4 prevented macrophage infiltration to brain endothelial cells by blocking CCL2 action after an ischemic stroke [ 48 ]. Importantly, high CCL2 levels have been reported in the ascitic fluid of OC patients [ 49 ].…”

Neural stem cell therapy for stroke: A multimechanistic approach to restoring neurological function

“…Stroke injury is propagated by a strong immune and inflammatory response through the activation of microglia, the resident immune cells of the brain, which produce pro‐inflammatory cytokines such as interleukin (IL)‐1β, IL‐6, and tumor necrosis factor‐alpha (TNF‐α) in response to damage‐associated molecular patterns (DAMPS) within minutes after onset of ischemia (Hossmann, ; Jin, Yang, & Li, ; Xiong, Liu, & Yang, ). Furthermore, the release of cytokines by activated microglia upregulates the expression of chemokines such as monocyte chemoattractant protein‐1 (MCP‐1) and chemokine ligand 1 (CXCL1) on endothelial cells, which promotes the infiltration of peripheral monocytes/macrophages across the blood–brain barrier (BBB) which exacerbates inflammatory injury (Remus, Sayeed, Won, Lyle, & Stein, ). The modulation of this inflammatory cascade may be the most widely characterized NSC mode of action in preclinical animal models of stroke.…”