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TLR2 Potentiates SR-Marco-Mediated Neuroinflammation by Interacting with the SRCR Domain

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Abstract

Microglial activation-induced neuroinflammation is critical in the pathogenesis of neurodegenerative diseases. Activated microglia are regulated mainly by innate pattern recognition receptors (PRRs) on their surface, of which macrophage receptor with collagenous structure (Marco) is a well-characterized scavenger receptor constitutively expressed on specific subsets of macrophages, including microglia. Increasing evidence has shown that Marco is involved in the pathogenesis of a range of inflammatory processes. However, research on the role of Marco in regulating neuroinflammation has reported conflicting results. In the present study, we examined the role Marco played in triggering neuroinflammation and its underlying mechanisms. The results demonstrated that silencing the Marco gene resulted in a significantly reduced neuroinflammatory response and vice versa. α-Syn stimulation in Marco overexpressing cells induced a pronounced inflammatory response, suggesting that Marco alone could trigger an inflammatory response. We also found that TLR2 significantly promoted Marco-mediated neuroinflammation, indicating TLR2 was an important co-receptor of Marco. Knocking down the TLR2 gene in microglia and mouse substantia nigra resulted in decreased expression of Marco. Subsequent mechanistic studies showed that deleting the SRCR domain of Marco resulted in disruption of the inflammatory response and the interaction between TLR2 and Marco. This suggested that TLR2 binds directly to the SRCR domain of Marco and regulates Marco-mediated neuroinflammation. In summary, this investigation revealed that TLR2 could potentiate Marco-mediated neuroinflammation by interacting with the SRCR domain of Marco, providing a new target for inhibiting neuroinflammation in neurodegenerative diseases.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

PRRs:

Pattern recognition receptors

Marco:

Macrophage receptor with collagenous structure

α-Syn:

α-Synuclein

TLR:

Toll-like receptors

CNS:

Central nervous system

AD:

Alzheimer’s disease

PD:

Parkinson’s disease

NLR:

NOD-like receptors

SR:

Scavenger receptors

SRCR:

SR cysteine-reach

NO:

Nitric oxide

Iba-1:

Ionized calcium binding adaptor molecule-1

DAB:

Diaminobenzidine

Co-IP:

Co-immunoprecipitation

MyD88:

Myeloid differentiation factor88

AP-1:

Transcription factors activator protein-1

NF-κB:

Nuclear factor kappa-B

MAPK:

Mitogen-activated protein kinase

LOX-1:

Lectin-type oxidized LDL receptor 1

KpOmpA:

Klebsiella pneumoniae

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Acknowledgements

First, I would like to extend my sincere gratitude to my supervisor, Xiu-Qi Bao and Dan Zhang, for their instructive advice and useful suggestions on my thesis. I am deeply grateful of their help in the completion of this thesis. I am also deeply indebted to all the other tutors and teachers in Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College for their direct and indirect help to me. Special thanks should go to my friends who have put considerable time and effort into their comments on the draft. Finally, I am indebted to my parents for their continuous support and encouragement.

Funding

This work was supported by grants from the National Sciences Foundation of China (81630097, 81773718), CAMS Innovation Fund for Medical Sciences (No. 2016-I2M-3–011), National Major Scientific and Technological Special Project for “Significant New Drugs Development” during the Thirteen Five-year Plan Period (2018ZX09711001-008–005, 2018ZX09711001-003–005, 2018ZX09711001-003–020), and CAMS The Fundamental Research Funds for the Central Universities (2018RC350002).

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Authors and Affiliations

  1. Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Xian Nong Tan Street, Beijing, 100050, China

    Lu Wang, Han-Yu Yang, Cai-Xia Zang, Jun-Mei Shang, Hui Liu, Zi-Hong Zhang, Fang-Yu Yuan, Cheng Ju, Fang-Yuan Li, Xiu-Qi Bao & Dan Zhang

  2. State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Xian Nong Tan Street, Beijing, 100050, China

    Lu Wang, Han-Yu Yang, Cai-Xia Zang, Jun-Mei Shang, Hui Liu, Zi-Hong Zhang, Fang-Yu Yuan, Cheng Ju, Fang-Yuan Li, Xiu-Qi Bao & Dan Zhang

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  1. Lu Wang
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Contributions

LW, X-QB, and DZ contributed to the conception of the study.

LW performed the experiment and data analyses and wrote the manuscript.

H-YY, C-XZ, J-MS, HL, Z-H Z, F-Y Y, CJ, and F-Y L provided help for the experiment.

Corresponding authors

Correspondence to Xiu-Qi Bao or Dan Zhang.

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Efforts were made to minimize animal suffering and to reduce the number of animals used. All animal experiments were performed in accordance with the National Institutes of Health guide for the care and use of laboratory animals.

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Not applicable.

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The authors declare no competing interests.

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Wang, L., Yang, HY., Zang, CX. et al. TLR2 Potentiates SR-Marco-Mediated Neuroinflammation by Interacting with the SRCR Domain. Mol Neurobiol 58, 5743–5755 (2021). https://doi.org/10.1007/s12035-021-02463-1

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