On September 27th, Yu Xiang Research Group of the Institute of Neuroscience of the Chinese Academy of Sciences, Center for Excellence in Brain Science and Intelligent Technology, and the National Key Laboratory of Neuroscience published an online paper entitled "Rapid transmission of peripheral infection signals by PDGFR beta cells to the central nervous system through chemochemical cCL2" in the journal Neuron.
the study found that in the early stages of systemic infection, PDGFR beta cells in the mouse brain quickly sensed infection signals in the circulatory system and enhanced the excitatory synaptic transmission and discharge frequency of neurons in multiple brain regions by releasing the chemofactor CCL2.
PDGFR beta cells is a blood vessel side cell, is an important part of the brain's neurovascular unit and blood-brain barrier, with the functionof of maintaining the blood-brain barrier, regulating blood flow of blood vessels and so on.
nervous system, immune system and circulatory system have a close relationship with each other. Recent studies
show that immune cells and the factors they secrete can cross the blood-brain barrier under physiological and pathological conditions, more and more classical immunogenic factors have been found to play an important role in neurodevelopment and synaptic plasticity, and cells of the immune system and nervous system can regulate each other.
the intercoscity of the nervous system, immune system and circulatory system is particularly important in infectious diseases.
for children under five years of age, infection is the main cause of death.
system inflammation that is not effectively controlled can lead to central nervous system diseases such as encephalitis, meningitis, and convulsions. Neuroinflammation in
neonatal period has also been reported to be associated with the onset of stunting, epilepsy, autism spectrum disorder, schizophrenia and other diseases.
previous studies of neuroinflammation focused on the response to later inflammation, including the activation of small glial cells and astrocytes, the invasion of the brain in substance of white blood cells, and the role of cytokines associated with cell secretion.
large amounts of cytokines (CCL2, etc.) can be detected in the early stages of infection (2 hours), and pathological behaviors (sickness behavior) caused by infection are also present in the early stages of infection.
However, due to the presence of the blood-brain barrier, small glial cells and astrocytes are not fully activated in the early stages of systemic infection, so these two cells are not the main source of CCL2.
what kind of cells are produced by so many cytokines? Is there a particular cell that can quickly feel the signal of peripheral infection and transmit it to the central nervous system, affecting the function of the brain? By establishing an inflammatory model of mouse systems that simulate bacterial or viral infections, Yu Xiang's research group, Duan Lihui and Zhang Xiaoxuan found that CCL2 (aka MCP-1) of PDGFR beta cell secretion was highly expressed in the early stages of inflammation.
used a variety of genetically modified mouse models, combined with in situ hybridization and immunohistochemical, and conditional knockout of Ccl2 in PDGFR beta cells (Pdgfrb-Cre; Ccl2fl/fl), they verified the result.
further discovery through single-cell sequencing that Col1a1 or Rgs5 subtypes of PDGFR beta cells express ccl2 highly in early inflammation.
single-cell sequencing results also show that PDGFR beta cells also simultaneously express a variety of cytokines other than Ccl2.
(A) system infection (LPS stimulation for 2 hours) results in high expression of CCL2 in PDGFR beta cells.
(B) specifically knocked ccl2 out of mice (Pdgfrb-Cre; Ccl2fl/fl), after inducing inflammation of the system, the content of CCL2 in hippocampus tissue and cerebrospinal fluid was significantly reduced.
(C, D) single-cell sequencing showed that Ccl2 was expressed mainly in two subgroups of PDGFR beta cells, Col1a1 and Rgs5.
(E) LPS processing can enhance neuronal excitable synaptic transmission; Ccl2fl/fl-in mice were significantly inhibited.
(F) pattern diagram. what physiological function does CCL2 have
pDGFR beta cells? Brain electrophysiological experiments have shown that CCL2 can act on glutamate energy neurons in multiple brain regions, improving their excitatory synaptic transmission, thereby improving their overall excitability.
cultured human cerebrovascular peripheral cells can release CCL2 with the stimulation of LPS or Poly (I:C), and incubating acute brain tablets with their cell culture can also lead to increased excitatory synaptic transmission and increased excitability of glutamate neurons in multiple brain regions.
use Pdgfrb-Cre; Ccl2fl/fl mice, after knocking Ccl2 out of PDGFR beta cells, the enhanced and pathological behavior of excitatory synaptic transmission caused by LPS injection seision was also effectively suppressed.
the main experiments of the above study were completed in developing mice, but the main findings can be repeated in adult and elderly mice, suggesting that the above mechanism has broad spectrum.
, the results reveal for the first time that PDGFR beta cells, as the brain's rapid response to external infections, can quickly sense extrinsic infections and inflammation, and transmit this signal to the brain.
the work is also the first to report that PDGFR beta cells regulate the excitability of neurons.
whether other factors secreted by CCL2 or PDGFR beta cells affect the activation of small glial cells and astrocytes in the later stages of nerve inflammation, to be further studied.
as the type of cell in the brain that first perceives and reacts to inflammation of the system, PDGFR beta cells (Col1a1 and/or Rgs5 subtypes) are potential new targets for the treatment of central nervous system infections.
because of its special location in the interface between the brain's substance and circulatory system, drugs targeting blood-brain barrier senile cells such as PDGFR beta cells have the advantage of not having to cross the blood-brain barrier.
the research was completed by Ph.D. graduate students Duan Lihui and Zhang Xiaoxuan under the guidance of researcher Yu Xiang, and laboratory member Miao Wanying made important contributions to the study.
the research was supported by the Ministry of Science and Technology's Key Research and Development Program (2016 YFA0501000), the National Natural Science Foundation of China (31530030) and the Shanghai Outstanding Discipline Leaders Program (16XD1404800).
Source: Shanghai Institute of Life Sciences.