MMPs and NETs are detrimental in CNS-tuberculosis with MMP inhibitor doxycycline improving murine CNS-tuberculosis survival
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ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE244089 | GEO | 2025/10/15
REPOSITORIES: GEO
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Project description:Despite effective anti-tuberculous treatment (ATT), up to 40% of patients with central nervous system tuberculosis (CNS-TB) suffer permanent neurological deficits and death. Immunopathology in CNS-TB, characterized by extensive brain inflammation and tissue destruction, is driven by a matrix-degrading phenotype, which results from an increase in matrix metalloproteinases (MMPs) relative to their tissue-specific inhibitors (tissue inhibitor of metalloproteinases, TIMPs). The immunopathological mechanism of CNS-TB remains undefined, hindering the development of new CNS-TB therapies. By performing laser capture microdissection RNA sequencing (LCM-RNA Seq), we profiled the spatial transcriptome of murine CNS-TB (M.tb H37Rv-infected C57BL6 Nos2-/- mice) and healthy murine (C57BL6 Nos2-/- mice) as control. The granulomas from murine CNS-TB treated with ATT alone, ATT with SB-3CT (MMP-2/9-specific MMP inhibitor), and ATT with doxycycline (broad spectrium MMP-inhibitor) were also profiled. Genes implicated in defense, immune, inflammatory and cytokine responses, neutrophil degranulation, antigen presentation and Toll-Like Receptor cascades, present predominantly in CNS-TB granulomas relative to other tissue types. On the other hand, genes relate to trans-synaptic signaling, synapse and cell junction organisation, neuron development and differentiation had decreased expression in murine CNS-TB inflammatory and granuloma tissues. We also found an increased expression of genes involve in response to oxidative stress, apoptosis and programmed cell death in murine CNS-TB treated with ATT plus adjunctive MMP inhibitors.
2025-10-15 | GSE244086 | GEO
Project description:Despite effective anti-tuberculous treatment (ATT), up to 40% of patients with central nervous system tuberculosis (CNS-TB) suffer permanent neurological deficits and death. The immunopathological mechanism of CNS-TB remains undefined, hindering the development of new CNS-TB therapies. We here report the spatial transcriptomics profiling of human CNS-TB and demyelination CNS tissues using laser capture microdissection RNA sequencing (LCM-RNA Seq). Human CNS-TB and demyelination samples exhibited distinct gene expression profiles based on cellular phenotypes. Genes involved in biological processes relates to cytokine responses, cell-substrate adhesion, extracellular matrix organization, inflammatory and immune responses are highly expressed in both inflammatory and granuloma tissues in contrast to demyelination and normal tissues. Down-regulated genes are associated with CNS-related processes such as synapse and cell junction organisation, myelination, neuron development and differentiation.
2025-10-15 | GSE244085 | GEO
Project description:MMPs and NETs are detrimental in CNS-tuberculosis with MMP inhibitor doxycycline improving murine CNS-tuberculosis survival
| PRJNA1021208 | ENA
Project description:MMPs and NETs are detrimental in CNS-tuberculosis with MMP inhibitor doxycycline improving murine CNS-tuberculosis survival (human)
| PRJNA1021211 | ENA
Project description:MMPs and NETs are detrimental in CNS-tuberculosis with MMP inhibitor doxycycline improving murine CNS-tuberculosis survival (mouse)
| PRJNA1021212 | ENA
Project description:ObjectivesTo describe the effect of combined oral contraceptives (COCs) on matrix metalloproteinases MMP-2 and MMP-9 activity and compare MMP activity in women taking a COC with or without doxycycline.Study designSubjects (n=20) underwent endometrial biopsies (1) in the late luteal phase of a baseline cycle prior to initiating COCs, (2) on days 19-21 while taking COCs in a standard 28-day cycle (7-day hormone-free interval) and (3) on days 26-28 while taking active COCs continuously for a 28-day cycle. During the continuous COC cycle, they were randomized to receive daily subantimicrobial dose doxycycline 40mg or placebo.ResultsCompared to baseline, COC treatment increased MMP-2 (p<.001) and MMP-9 (p<.001). MMP activity was lower in subjects taking a COC with doxycycline compared to those receiving placebo although only significantly lower for MMP-2 latent form (p=.002).ConclusionsUnscheduled bleeding with COCs may be the result of increased endometrial MMPs. Sample size limitations prevent us from determining how doxycycline affects MMP activity in COC users.
| S-EPMC4841248 | biostudies-literature
Project description:Tuberculosis (TB) of the central nervous system (CNS) is a deadly disease characterized by extensive tissue destruction, driven by molecules such as Matrix Metalloproteinase-2 (MMP-2) which targets CNS-specific substrates. In a simplified cellular model of CNS TB, we demonstrated that conditioned medium from Mycobacterium tuberculosis-infected primary human monocytes (CoMTb), but not direct infection, unexpectedly down-regulates constitutive microglial MMP-2 gene expression and secretion by 72.8% at 24 hours, sustained up to 96 hours (P < 0.01), dependent upon TNF-α. In human CNS TB brain biopsies but not controls the p38 pathway was activated in microglia/macrophages. Inhibition of the p38 MAP kinase pathway resulted in a 228% increase in MMP-2 secretion (P < 0.01). In contrast ERK MAP kinase inhibition further decreased MMP-2 secretion by 76.6% (P < 0.05). Inhibition of the NFκB pathway resulted in 301% higher MMP-2 secretion than CoMTb alone (P < 0.01). Caspase 8 restored MMP-2 secretion to basal levels. However, this caspase-dependent regulation of MMP-2 was independent of p38 and NFκB pathways; p38 phosphorylation was increased and p50/p65 NFκB nuclear trafficking unaffected by caspase 8 inhibition. In summary, suppression of microglial MMP-2 secretion by M.tb-infected monocyte-dependent networks paradoxically involves the pro-inflammatory mediators TNF-α, p38 MAP kinase and NFκB in addition to a novel caspase 8-dependent pathway.
| S-EPMC3113956 | biostudies-literature
Project description:Background and purposeRecent reports from our laboratory demonstrated the post-ischaemic expression profile of various matrix metalloproteinases (MMPs) in rats and the detrimental role of MMP-12 in post-stroke brain damage. We hypothesise that the post-stroke dysregulation of MMPs is similar across species and that genetic deletion of MMP-12 would not affect the post-stroke expression of other MMPs. We tested our hypothesis by determining the pre-ischaemic and post-ischaemic expression profile of MMPs in wild-type and MMP-12 knockout mice.MethodsFocal cerebral ischaemia was induced in wild-type and MMP-12 knockout mice by middle cerebral artery occlusion procedure by insertion of a monofilament suture. One hour after ischaemia, reperfusion was initiated by removing the monofilament. One day after reperfusion, ischaemic brain tissues from various groups of mice were collected, and total RNA was isolated and subjected to cDNA synthesis followed by PCR analysis.ResultsAlthough the post-stroke expression profile of MMPs in the ischaemic brain of mice is different from rats, there is a clear species similarity in the expression of MMP-12, which was found to be predominantly upregulated in both species. Further, the post-stroke induction or inhibition of various MMPs in MMP-12 knockout mice is different from their respective expression profile in wild-type mice. Moreover, the brain mRNA expression profile of various MMPs in MMP-12 knockout mice under normal conditions is also different to their expression in wild-type mice.ConclusionsIn the ischaemic brain, MMP-12 upregulates several fold higher than any other MMP. Mice derived with the genetic deletion of MMP-12 are constitutive and have altered MMP expression profile both under normal and ischaemic conditions.
| S-EPMC6169614 | biostudies-literature
Project description:BACKGROUNDMatrix metalloproteinases (MMPs) are key regulators of tissue destruction in tuberculosis (TB) and may be targets for host-directed therapy. We conducted a phase II double-blind, randomized, controlled trial investigating doxycycline, a licensed broad-spectrum MMP inhibitor, in patients with pulmonary TB.METHODSThirty patients with pulmonary TB were enrolled within 7 days of initiating anti-TB treatment and randomly assigned to receive either 100 mg doxycycline or placebo twice a day for 14 days, in addition to standard care.RESULTSWhole blood RNA-sequencing demonstrated that doxycycline accelerated restoration of dysregulated gene expression in TB towards normality, rapidly down-regulating type I and II interferon and innate immune response genes, and up-regulating B-cell modules relative to placebo. The effects persisted for 6 weeks after doxycycline discontinuation, concurrent with suppressed plasma MMP-1. Doxycycline significantly reduced sputum MMP-1, -8, -9, -12 and -13, suppressed type I collagen and elastin destruction, reduced pulmonary cavity volume without altering sputum mycobacterial loads, and was safe.CONCLUSIONAdjunctive doxycycline with standard anti-TB treatment suppressed pathological MMPs in PTB patients. Larger studies on adjunctive doxycycline to limit TB immunopathology are merited.TRIAL REGISTRATIONClinicalTrials.gov NCT02774993.FUNDINGSingapore National Medical Research Council (NMRC/CNIG/1120/2014, NMRC/Seedfunding/0010/2014, NMRC/CISSP/2015/009a); the Singapore Infectious Diseases Initiative (SIDI/2013/013); National University Health System (PFFR-28 January 14, NUHSRO/2014/039/BSL3-SeedFunding/Jul/01); the Singapore Immunology Network Immunomonitoring platform (BMRC/IAF/311006, H16/99/b0/011, NRF2017_SISFP09); an ExxonMobil Research Fellowship, NUHS Clinician Scientist Program (NMRC/TA/0042/2015, CSAINV17nov014); the UK Medical Research Council (MR/P023754/1, MR/N006631/1); a NUS Postdoctoral Fellowship (NUHSRO/2017/073/PDF/03); The Royal Society Challenge Grant (CHG\R1\170084); the Sir Henry Dale Fellowship, Wellcome Trust (109377/Z/15/Z); and A*STAR.
| S-EPMC8321570 | biostudies-literature
Project description:Primary central nervous system lymphoma (PCNSL) is an aggressive disease with previously poor prognosis. The advent of high-dose methotrexate-based induction regimens as well as use of consolidation therapy has greatly improved this prognosis in recent decades, but durable remission still eludes half of patients. In this review, we summarize the progress made in the treatment of PCNSL as well as the challenges that remain, with a focus on defining optimal induction and consolidation regimens, including the promise of developing biotherapies. Future studies will help delineate the best combination of existing and novel treatment strategies, with the goal of expanding the cohort of patients achieving a cure.
| S-EPMC10481403 | biostudies-literature