Chronic systemic infection exacerbates ischemic brain damage via a CCL5 (regulated on activation, normal T-cell expressed and secreted)-mediated proinflammatory response in mice.
Infection and systemic inflammation are risk factors for cerebrovascular diseases and poststroke infections impair outcome in stroke patients, although the mechanisms of their contribution are mostly unknown. No preclinical studies have identified how chronic infection affects ischemic brain damage and which key inflammatory mediators are involved. We used a well established model of gut infection (Trichuris muris) to study how chronic infection contributes to brain injury. We show that, in mice, infection that leads to a chronic Th1-polarized immune response dramatically (60%) exacerbates brain damage caused by experimental stroke. Chronic Th1-type infection resulted in systemic upregulation of proinflammatory mediators and profoundly altered stroke-induced early (40 min to 4 h) and late (48 h) inflammation in the brain and peripheral tissues. Using the same infection, we show that a Th1-, but not Th2-polarized response augments brain injury by increasing the Th1 chemokine CCL5 [regulated on activation, normal T-cell expressed and secreted (RANTES)] systemically. This infection-associated response paralleled altered regulatory T-cell response, accelerated platelet aggregation in brain capillaries, and increased microvascular injury and matrix metalloproteinase activation after stroke. Antibody neutralization of RANTES reversed the effect of chronic infection on brain damage, microvascular MMP-9 activation, and cellular inflammatory response. Our results suggest that chronic infection exacerbates ischemic brain damage via a RANTES-mediated systemic inflammatory response, which leads to delayed resolution of inflammation and augmented microvascular injury in the brain.
Dénes
Adám
A
Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester, United Kingdom.
Humphreys
Neil
N
Lane
Thomas E
TE
Grencis
Richard
R
Rothwell
Nancy
N
D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D001812:Blood-Brain Barrier / Q000503:physiopathology; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology; D001930:Brain Injuries / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D020214:Cerebrovascular Trauma / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D018946:Chemokine CCL5 / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005434:Flow Cytometry / Q000379:methods; D007839:Functional Laterality; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D007249:Inflammation / Q000150:complications* / Q000188:drug therapy / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009422:Nervous System Diseases / Q000209:etiology; D040201:Platelet Membrane Glycoprotein IIb / Q000378:metabolism; D011897:Random Allocation; D013601:T-Lymphocytes; D013997:Time Factors; D014257:Trichuriasis / Q000150:complications; D015854:Up-Regulation / Q000276:immunology
D000906:Antibodies; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D016207:Cytokines; D009419:Nerve Tissue Proteins; D040201:Platelet Membrane Glycoprotein IIb; D020780:Matrix Metalloproteinase 9