MMPs and NETs are detrimental in CNS-tuberculosis with MMP Inhibition in CNS-tuberculosis mice improving survival PMID: 41076519

ADC Targets in Oncology

2026-04-10

MMPs and NETs are detrimental in CNS-tuberculosis with MMP Inhibition in CNS-tuberculosis mice improving survival

J Neuroinflammation. 2025 Oct 11;22(1):230. doi: 10.1186/s12974-025-03548-7.

Xuan Ying Poh ^# ¹ , Fei Kean Loh ^# ¹ , Chen Bai ¹ , Hai Tarng Chong ¹ , Wei Keat Teo ² , Yi Hao Wong ¹ , Jia Mei Hong ¹ , Qing Hao Miow ¹ , Pei Min Thong ¹ , Bryce Vilaysane ³ , Ting Huey Hu ¹ , Srishti Chhabra ⁴ , Yu Wang ¹ , Siew Ching Tiong ⁵ , Siew Moy Fong ⁶ , Masako Kamihigashi ⁷ , Ravisankar Rajarethinam ⁸ , Wen Donq Looi ⁹ , Esther Sok Hwee Cheow ¹⁰ , Glenn Kunnath Bonney ¹⁰ ¹¹ , Leroy Sivappiragasam Pakkiri ¹² , Chester Lee Drum ¹² , Yan Fen Peng ¹³ , Ming Lee ¹⁴ , Char Loo Tan ¹⁵ , Cristine Szu Lyn Ding ¹⁶ , Tchoyoson Choie Cheio Lim ¹⁷ ¹⁸ , Tsin Wen Yeo ¹⁹ , Joshua K Tay ²⁰ , Andres F Vallejo ²¹ , Catherine W M Ong ²² ²³ ²⁴

Affiliations

1. Infectious Diseases Translational Research Programme, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
2. Department of Otolaryngology-Head & Neck Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
3. Department of Biology, The University of Texas at Arlington, Arlington, Texas, USA.
4. Division of Infectious Diseases, Department of Medicine, National University Hospital, Singapore, Singapore.
5. Department of Diagnostic Radiology, Tan Tock Seng Hospital, Singapore, Singapore.
6. Division of Paediatric Infectious Diseases, Paediatric Department, Hospital Likas, Kota Kinabalu, Sabah, Malaysia.
7. Segawa Memorial Neurological Clinic for Children, Tokyo, Japan.
8. Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore.
9. Bruker Daltonics, Bruker Singapore Pte Ltd, Singapore, Singapore.
10. Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore, Singapore.
11. Department of Surgery, National University Hospital, Singapore, Singapore.
12. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
13. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
14. Department of Pathology, Singapore General Hospital, Singapore, Singapore.
15. Department of Pathology, National University Hospital, Singapore, Singapore.
16. Division of Anatomical Pathology, Changi General Hospital, Singapore, Singapore.
17. Department of Neuroradiology, National Neuroscience Institute, Singapore, Singapore.
18. Duke-NUS Medical School, Singapore, Singapore.
19. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
20. Department of Otolaryngology-Head & Neck Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. [email protected].
21. Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, Faculty of Medicine, University of Southampton, Southampton, UK. [email protected].
22. Infectious Diseases Translational Research Programme, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. [email protected].
23. Division of Infectious Diseases, Department of Medicine, National University Hospital, Singapore, Singapore. [email protected].
24. Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore, Singapore. [email protected].
# Contributed equally.

Abstract

Despite anti-tuberculous treatment (ATT), central nervous system tuberculosis (CNS-TB) still causes permanent neurological deficits and death. To identify prognostic factors, we profiled a prospective cohort of pediatric HIV-negative tuberculous meningitis (TBM) and non-TBM patients. We found significantly increased cerebrospinal fluid (CSF) Matrix Metalloproteinases (MMPs) and neutrophil extracellular traps (NETs) in TBM patients with neuroradiological abnormalities and poor outcomes. To dissect mechanisms, we used our existing CNS-TB murine model, which shows neutrophil-rich necrotizing pyogranulomas with MMP-9 and NETs colocalizing, as observed in human CNS-TB pathology. Spatial transcriptomic analysis of both human and murine CNS-TB demonstrates a highly-inflamed and neutrophil-rich microenvironment of inflammatory immune responses, extracellular matrix degradation and angiogenesis within CNS-TB granulomas. Murine CNS-TB treated with ATT and MMP inhibitors SB-3CT or doxycycline show significantly suppressed NETs with improved survival. MMP inhibition arms show attenuated inflammation and well-formed blood vessels within granulomas. Adjunctive doxycycline is highly promising to improve CNS-TB outcomes and survival.

Keywords

Central nervous system tuberculosis; Doxycycline; Host-directed therapy; Matrix metalloproteinases; Neutrophil extracellular trap.