Age-related CCL12 Aggravates Intracerebral Hemorrhage-induced Brain Injury via Recruitment of Macrophages and T Lymphocytes

Abstract

Circulating factors associated with aging have been shown to be involved in the development of age-related chronic and acute brain diseases. Here, we aimed to investigate the roles and mechanisms of CCL12, a circulating factor that is highly expressed in the plasma of aged rodents after intracerebral hemorrhage (ICH) using parabiosis and ICH models. Neurological deficit score (NDS), mortality rate, brain water content (BWC), and levels of inflammatory factors were determined to assess the degree of ICH-induced brain injury. Peripheral inflammatory cell infiltration was examined using immunofluorescence and flow cytometry. After confirming that acute brain injury after ICH was aggravated with age, we found that brain and plasma CCL12 levels were markedly higher in old mice than in young mice after ICH, and that plasma CCL12 was able to enter the brain. Using CCL12-/mice, we showed that the degree of damage in the brain-as determined by NDS, mortality rate, BWC, levels of inflammatory factors, and numbers of degenerative and apoptotic neural cells and surviving neurons was significantly attenuated compared to that observed in old wild-type (WT) mice. These effects were reversed in CCL12-treated old mice. The detrimental effects caused by CCL12 may involve its ability to recruit macrophages and T cells. Finally, the administration of an anti-CCL12 antibody markedly improved the outcomes of ICH mice. Our results are the first to indicate that elevated peripheral CCL12 levels in old mice aggravates ICH-induced brain injury by recruiting macrophages and T cells. Thus, CCL12 may be a new target for ICH treatment.

Functional Roles of Chemokine Receptor CCR2 and Its Ligands in Liver Disease

“…In addition, Yang et al reported that mCCL12 produced by injured alveolar epithelial cells could promote pulmonary fibrosis in mice by recruiting profibrotic macrophages through CCR2 in mice (102). The increased peripheral level of mCCL12 in old mice can aggravate brain injury induced by intracerebral hemorrhage by recruiting macrophages and T cells (103). In the tumor microenvironment, mCCL12 has been reported to play an essential role in tumor progression by regulating the recruitment and polarization of macrophages.…”

Formyl peptide receptor 1 signaling potentiates inflammatory brain injury

“…Besides IL-1, CCL5, and CCL12, other immune modulatory proteins were also reduced in Fpr1 −/− mice after ICH. The reduction of these factors may alleviate brain inflammation and promote neurorepair (36)(37)(38). The elevated blood mitochondria-derived N-formyl peptides could also activate circulating FPR1 + immune cells such as neutrophils and monocytes.…”

Interleukin‐18 mediated inflammatory brain injury after intracerebral hemorrhage in male mice

“…The needle was kept in position for an additional 5-min period and then slowly removed to prevent backflow. Exogenous IL-18 (20 μg/kg) was purchased from R&D systems (9139-IL-050/CF; RRID:AB-2895090), and it was injected 1 hr before inducing ICH according to previous description (Huang et al, 2020;Wu et al, 2020;Yang et al, 2018). The purity of recombinant mouse IL-18 was more than 90% by SDS-PAGE visualized with silver staining and quantitative densitometry by Coomassie® blue staining according to the manufacturer.…”