TNF‐α antagonism rescues the effect of ageing on stroke: Perspectives for targeting inflamm‐ageing

Abstract

Aims Epidemiologic evidence links ischemic stroke to age, yet the mechanisms that underlie the specific and independent effects of age on stroke remain elusive, impeding the development of targeted treatments. This study tested the hypothesis that age directly aggravates stroke outcomes and proposes inflamm‐aging as a mediator and potential therapeutic target. Methods 3 months‐ (young) and 18‐20 months‐old (old) mice underwent transient middle cerebral artery occlusion (tMCAO) for 30 minutes followed by 48 hours of reperfusion. Old animals received weekly treatment with the TNF‐α neutralizing antibody adalimumab over 4 weeks before tMCAO in a separate set of experiments. Plasma levels of TNF‐ α were assessed in patients with ischemic stroke and correlated with age and outcome. Results Old mice displayed larger stroke size than young ones with increased neuromotor deficit. Immunohistochemical analysis revealed impairment of the blood‐brain barrier in old mice, i.e. increased post‐stroke degradation of endothelial tight junctions and expression of tight junctions‐digesting and neurotoxic matrix metalloproteinases. At baseline, old animals showed a broad modulation of several circulating inflammatory mediators. TNF‐α displayed the highest increase in old animals and its inhibition restored the volume of stroke, neuromotor performance, and survival rates of old mice to the levels observed in young ones. Patients with ischemic stroke showed increased TNF‐α plasma levels which correlated with worsened short‐term neurological outcome as well as with age. Conclusions This study identifies TNF‐α as a causative contributor to the deleterious effect of aging on stroke and points to inflamm‐aging as a mechanism of age‐related worsening of stroke outcomes and potential therapeutic target in this context. Thus, this work provides a basis for tailoring novel stroke therapies for the particularly vulnerable elderly population.

Inflammatory biomarkers of ischemic stroke

“…In accordance with its potential dual role, TNF-α inhibition in experimental models of ischemic stroke showed both beneficial and detrimental effects on stroke size and neurological deficit [ 3 ]. Specifically, timing of intervention as well as specific animal model characteristics (such as age, inflammation levels and permanent vs. transient ischemia) have been associated with different outcomes [ 2 , 4 ]. While TNF-α inhibition may be beneficial on stroke size and neuromotor deficit at short-term ischemia/reperfusion injury, such a protective effect seems lost when looking at long-term outcome, such as post-stroke neuronal plasticity.…”

Neutrophils in aging and aging‐related pathologies

“…Further, older patients show increased intra‐cerebral neutrophils, extracellular matrix‐degrading matrix metalloproteinase‐9 (MMP‐9) expression, and elevated hemorrhagic transformation when compared to younger stroke patients 203 . Preclinical studies confirm aging as a substantial determinant of stroke outcome 210 . Indeed, young, middle‐aged, and aged mice subjected to experimental stroke show worsened functional outcome with aging accompanied by increased immigration of neutrophils, macrophages, dendritic cells, and increased activation of resident microglia 211 .…”

Circulating Leukocyte as an Inflammatory Biomarker: Association with Fibrinogen and Neuronal Damage in Acute Ischemic Stroke

“…In post-stroke inflammation, tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6) are usually referred as primary pro-inflammatory cytokines, and are investigated as essential signaling proteins secreted by endothelial cells, immune cells, oligodendrocytes, and astrocytes in central nervous system. [18][19][20] Clinical studies show that higher plasma levels of TNF-α, IL-1β, and IL-6 are associated with serious inflammation and adverse outcome of ischemic stroke. 21 Both circulating fibrinogen and C-reactive protein (CRP) are non-specific inflammatory mediators originated from liver.…”