Wednesday, February 5, 2025
2/5/2025
ABSTRACT Intracerebral hemorrhage (ICH) leads to severe brain damage, profound deficit, and death in ~40% of patients, and aging is a key risk factor for poor outcome. At least 30% of ICH patients develop lung injury, including lung infection and these patients have worse outcome. This implies that stroke, especially in aged population, affects lung health, which may influence the stroke outcome. While the cause is multifactorial, aberrant immune (age- and ICH-driven) responses play key role. Plasma CC-motif chemokine 11 (CCL11) increases with aging and the principal receptor for CCL11 is CC-motif chemokine receptor 3 (CCR3). CCR3 expression on neutrophils (PMNs) is low, however, under stress to lung and in presence of CCL11, the CCR3 on lung PMNs is induced. These CCR3+ PMNs acquire “damaging” phenotype. With lung being one of largest reservoirs of PMNs, the CCR3+ PMNs upon release from lung could enter the ICH-affected brain and augment ICH injury. Besides PMNs, CCR3 is expressed by microglia (MG), cells that are ultimately needed for hematoma clearance and brain repair, but if polarized to the “damaging” type MG could contribute to adjacent tissue injury. Thus, aging elevated CCL11 can robustly alter MG function impacting ICH. Our preliminary results demonstrate: Elevation of CCL11 levels (by systemic repetitive delivery of CCL11 to simulate aging) in mice increases PMNs in lung and increases their CCR3 expression. Lung PMNs from CCR3 knockout have suppressed “damaging” phenotype. Aging or ICH activates CCR3 expression on lung PMNs. CCL11 delivered to lung of young mice subjected to ICH increases PMNs in the lung and aggravates neurological deficits caused by ICH. PMNs from lung can infiltrate ICH-affected brain and PMNs depletion selectively in lung of aged mice reduces brain infiltration of PMNs and mitigates neurological deficits after ICH. Systemic delivery of a CCL11-neutralizing antibody (CCL11NA) into aged ICH mice reduces neurological deficits, PMNs influx to ICH-affected brain, and it improves hematoma clearance. In the aged brain, CCR3 is mainly found in MG. In MG, CCL11 reduces MnSOD expression and impairs phagocytic function by downregulating PPAR and its target genes signifying a pro-inflammatory phenotype, and this is reversed with CCR3 inhibition. Our hypothesis is: In aged animals, that have elevated CCL11, in response to ICH, (1) lung PMNs shift to CCR3+ “damaging” type and infiltrate the brain after ICH, and (2) CCR3+ MG lose their “reparative” role (phagocytic/anti-inflammatory/anti-oxidative). Together these augment ICH-induced damage. We predict that inhibition of CCL11/CCR3 signaling will reverse this deleterious cascade and promote repair. Our Aims are to define a role of age-enhanced CCL11/CCR3 signaling in lung PMN-mediated ICH pathology and to determine if CCL11/CCR3 inhibition reveres age-associated “damaging” MG phenotype in ICH injury. We stress that this study will establish a novel target for ICH treatment for elderly patients, based on understanding pathological role of CCL11/CCR3 signaling.
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