Microglia-derived CCL2 has a prime role in neocortex neuroinflammation

Abstract

Background In myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), several areas of demyelination are detectable in mouse cerebral cortex, where neuroinflammation events are associated with scarce inflammatory infiltrates and blood–brain barrier (BBB) impairment. In this condition, the administration of mesenchymal stem cells (MSCs) controls neuroinflammation, attenuating astrogliosis and promoting the acquisition of stem cell traits by astrocytes. To contribute to the understanding of the mechanisms involved in the pathogenesis of EAE in gray matter and in the reverting effects of MSC treatment, the neocortex of EAE-affected mice was investigated by analyzing the cellular source(s) of chemokine CCL2, a molecule involved in immune cell recruitment and BBB-microvessel leakage. Methods The study was carried out by immunohistochemistry (IHC) and dual RNAscope IHC/in situ hybridization methods, using astrocyte, NG2-glia, macrophage/microglia, and microglia elective markers combined with CCL2. Results The results showed that in EAE-affected mice, hypertrophic microglia are the primary source of CCL2, surround the cortex neurons and the damaged BBB microvessels. In EAE-affected mice treated with MSCs, microgliosis appeared diminished very soon (6 h) after treatment, an observation that was long-lasting (tested after 10 days). This was associated with a reduced CCL2 expression and with apparently preserved/restored BBB features. In conclusion, the hallmark of EAE in the mouse neocortex is a condition of microgliosis characterized by high levels of CCL2 expression. Conclusions This finding supports relevant pathogenetic and clinical aspects of the human disease, while the demonstrated early control of neuroinflammation and BBB permeability exerted by treatment with MSCs may have important therapeutic implications.

Markers of blood-brain barrier disruption increase early and persistently in COVID-19 patients with neurological manifestations

“…Maladaptive microglia and monocyte activation may also exert a detrimental effect on BBB function and integrity in COVID-19 ( 14 ). Interestingly, a recent publication has shown that microglia−derived chemokine MCP-1 (also known as CCL2) seems to have a major role in neocortex neuroinflammation and BBB disruption in a mouse model of autoimmune encephalomyelitis ( 48 ). Moreover, high blood MCP-1 levels have been associated with disease severity and mortality in COVID-19 ( 49 ).…”

Neuroblasts migration under control of reactive astrocyte-derived BDNF: a promising therapy in late neurogenesis after traumatic brain injury

“…CCL2 is known to be up-regulated under various pathological conditions, including TBI, impairing the integrity of the blood–brain barrier (BBB) [47 , 48] . CCL2 also initiates an inflammatory response after brain injury through recruitment of microglia and macrophage to the area of injury [49 – 51] . Whether and how these processes interfere with the endogenous mechanism of BDNF function and neuroblasts migration need further investigation.…”

The ins and outs of microglial cells in brain health and disease

“…In addition, a recent study demonstrated the pivotal role of microglia in neocortex inflammation since they produce and secrete CCL2, a chemokine involved in immune cell recruitment and BBB-microvessel leakage. Notably, decreased MG-CCL2 expression was associated with a more restored BBB and diminished neuroinflammation ( 52 ). It is important to note that the immune status, referred to as polarization of microglia or macrophages, will be determined by the net effect of a variety of pro-inflammatory and anti-inflammatory stimuli, being the outcome of the response a balance between the strength of the detected signals.…”