Bone Marrow-Derived IL-1Ra Increases TNF Levels Poststroke

Abstract

Tumor necrosis factor (TNF) and interleukin-1 receptor antagonist (IL-1Ra) are key players in stroke, a disease in which cell-based therapies have shown great potential. Having shown an infarct-reducing effect of bone marrow (BM) cells, especially cells with high IL-1Ra expression, we here investigated the effect of BM cells on TNF and other stroke-related mediators in mice after transient middle cerebral artery occlusion (tMCAo) and in vitro using adult microglial cultures. We analyzed stroke-related genes and inflammatory mediators using qPCR stroke Tier panels, electrochemiluminescence, or enzyme-linked immunosorbent assays. We found a significant correlation and cellular colocalization between microglial-derived TNF and IL-1Ra, though IL-1Ra production was TNF independent. BM treatment significantly increased TNF, interleukin (IL)-10, and IL-4 levels, while C-X-C motif ligand 1 (CXCL1), IL-12p70, and Toll-like receptor 2 (TLR2) decreased, suggesting that BM treatment favors an anti-inflammatory environment. Hierarchical clustering identified Tnf and IL-1rn within the same gene cluster, and subsequent STRING analysis identified TLR2 as a shared receptor. Although IL-1Ra producing BM cells specifically modulated TNF levels, this was TLR2 independent. These results demonstrate BM cells as modulators of poststroke inflammation with beneficial effects on poststroke outcomes and place TNF and IL-1Ra as key players of the defense response after tMCAo.

The central role of peripheral inflammation in ischemic stroke

“…135,136 BMSCs with elevated IL-1 receptor antagonist expression notably reduce TNF levels and impact inflammation after stroke in mice. 134 Furthermore, BMSCs interact with T-regs, as noted above, to decrease inflammatory reactions to stroke in rats. 137 Other variations of BMSCs, hematopoietic stem cells and MSCs, are also shown to modulate immune cell infiltration and cytokine signaling in the brain in murine models.…”

“…Bone marrow contributions to peripheral inflammation can be mitigated by bone marrow derived stem cells. 28,54,116,118,119,125,126,129,133,134 Bone marrow-mononuclear cells (BMMCs) travel to the liver, lungs, spleen, kidneys, and bladder in patients with stroke and can mitigate stroke damage and neuronal death by modulating peripheral inflammation. 118,125,133 In addition to these migratory paths, BMSCs can also interact with other peripheral inflammation organ systems, such as the gut microbiome and adrenal glands in murine models.…”

Protein Biomarkers in Blood Reflect the Interrelationships Between Stroke Outcome, Inflammation, Coagulation, Adhesion, Senescence and Cancer

“…In the adult brain, TNF is mainly derived from glia, astrocytes, and microglia, and is involved in the regulation of neurotransmitter processes, cell division, blood-brain barrier permeability, leukocyte migration to the central nervous system and angiogenesis (Xue et al 2022). While increased intra-lesional TNF appears to be beneficial in the acute stroke stage (von Linstow et al 2021), permanently elevated TNF serum levels may indicate ongoing neuroinflammation driving continued cell death following stroke (Stuckey et al 2021). IL6 is also involved in the regulation of systemic and local (cerebral intra-and perilesional) inflammatory responses and has recently been identified as an independent predictor of recurrent stroke at 12 months even in patients with persistent adherence to guideline-based secondary stroke prevention (Pan et al 2021).…”