Key role of the CCR2-CCL2 axis in disease modification in a mouse model of tauopathy

Abstract

Background For decades, dementia has been characterized by accumulation of waste in the brain and low-grade inflammation. Over the years, emerging studies highlighted the involvement of the immune system in neurodegenerative disease emergence and severity. Numerous studies in animal models of amyloidosis demonstrated the beneficial role of monocyte-derived macrophages in mitigating the disease, though less is known regarding tauopathy. Boosting the immune system in animal models of both amyloidosis and tauopathy, resulted in improved cognitive performance and in a reduction of pathological manifestations. However, a full understanding of the chain of events that is involved, starting from the activation of the immune system, and leading to disease mitigation, remained elusive. Here, we hypothesized that the brain-immune communication pathway that is needed to be activated to combat tauopathy involves monocyte mobilization via the C-C chemokine receptor 2 (CCR2)/CCL2 axis, and additional immune cells, such as CD4+ T cells, including FOXP3+ regulatory CD4+ T cells. Methods We used DM-hTAU transgenic mice, a mouse model of tauopathy, and applied an approach that boosts the immune system, via blocking the inhibitory Programmed cell death protein-1 (PD-1)/PD-L1 pathway, a manipulation previously shown to alleviate disease symptoms and pathology. An anti-CCR2 monoclonal antibody (αCCR2), was used to block the CCR2 axis in a protocol that partially eliminates monocytes from the circulation at the time of anti-PD-L1 antibody (αPD-L1) injection, and for the critical period of their recruitment into the brain following treatment. Results Performance of DM-hTAU mice in short-term and working memory tasks, revealed that the beneficial effect of αPD-L1, assessed 1 month after a single injection, was abrogated following blockade of CCR2. This was accompanied by the loss of the beneficial effect on disease pathology, assessed by measurement of cortical aggregated human tau load using Homogeneous Time Resolved Fluorescence-based immunoassay, and by evaluation of hippocampal neuronal survival. Using both multiparametric flow cytometry, and Cytometry by Time Of Flight, we further demonstrated the accumulation of FOXP3+ regulatory CD4+ T cells in the brain, 12 days following the treatment, which was absent subsequent to CCR2 blockade. In addition, measurement of hippocampal levels of the T-cell chemoattractant, C-X-C motif chemokine ligand 12 (Cxcl12), and of inflammatory cytokines, revealed that αPD-L1 treatment reduced their expression, while blocking CCR2 reversed this effect. Conclusions The CCR2/CCL2 axis is required to modify pathology using PD-L1 blockade in a mouse model of tauopathy. This modification involves, in addition to monocytes, the accumulation of FOXP3+ regulatory CD4+ T cells in the brain, and the T-cell chemoattractant, Cxcl12.

Accelerated cognitive decline in obese mouse model of Alzheimer’s disease is linked to sialic acid-driven immune deregulation

“…In our previous work in 5xFAD mice, we have shown that brain disease progression is accompanied by increased Tregs in the periphery that interfere with recruitment of disease-resolving leukocytes into the brain by curtailing IFNg signaling at the choroid plexus 18,72 . In different mouse models (including 5xFAD), treatment that transiently reduced systemic Tregs or blocked the PD-1/PD-L1 inhibitory immune checkpoint pathway resulted in modification of disease course [18][19][20] and increased Tregs levels in the brain 18,71 .…”

“…The role of Tregs in neurodegeneration is controversial, as both protective [53][54][55][56][57][58] and harmful functions 18,57,[59][60][61] have been described, depending on location and timing 18,54,[62][63][64][65][66] . While Tregs within the brain can display anti-inflammatory activity 18,[67][68][69][70][71] , their elevation in the periphery might be harmful, as it blocks the ability of the brain to harness bone marrow-derived cells needed to clean the brain and resolve local inflammation 18 . In our previous work in 5xFAD mice, we have shown that brain disease progression is accompanied by increased Tregs in the periphery that interfere with recruitment of disease-resolving leukocytes into the brain by curtailing IFNg signaling at the choroid plexus 18,72 .…”

“…In our previous work in 5xFAD mice, we have shown that brain disease progression is accompanied by increased Tregs in the periphery that interfere with recruitment of disease-resolving leukocytes into the brain by curtailing IFNg signaling at the choroid plexus 18,72 . In different mouse models (including 5xFAD), treatment that transiently reduced systemic Tregs or blocked the PD-1/PD-L1 inhibitory immune checkpoint pathway resulted in modification of disease course 18–20 and increased Tregs levels in the brain 18,71 . In line with this previous evidence, and considering that aging, including immune aging, is the primary risk factor for AD 73 , the most parsimonious interpretation of our present findings is that 5xFAD mice had reduced resilience to the obesity-induced burden on the immune system, which in turn led to the exacerbation of brain pathology.…”

Insight Into Regulatory T Cells in Sepsis-Associated Encephalopathy

“…Blocking the programmed cell death Ligand 1 (PD-L1) pathway for 12 days in a DM-hTAU transgenic mice model (a mouse model of tauopathy), favored an increased accumulation of Foxp3 + T regs in the brain via the CCR 2/CCL 2 axis. Simultaneously, an improvement of the cognitive behavior, disease pathology (mainly phosphorylated tauopathy deposition in the hippocampus), neuronal survival and hippocampal inflammation, was also observed ( 89 ). Nevertheless, the increased accumulation of Foxp3 + T regs in the brain can also have detrimental effects.…”

“…For decades, dementia has been characterized by a buildup of waste in the brain and mild inflammation, and was shown to be influenced by the immune system ( 89 ). In a rat model of sepsis, exposure to LPS for 7 days leads to deposition of amyloid-β plaques and phosphorylated tauopathy in the hippocampus ( 23 , 109 ).…”