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Figure 3. Immune defense regulatory network mediated by Mtb EVs and HC EVs during Mtb infection. Mtb EVs activate macrophages via TLR2 signaling, triggering NF-κB pathway activation, pro-inflammatory cytokine (TNF-α, IL-6, IL-1β) secretion, and chemokine (CCL2, MCP-1) production to recruit immune cells. Host cell EVs, including exosomes and microvesicles, further amplify these defenses: macrophage-derived exosomes deliver host and Mtb RNA, activating the RIG-I pathway to induce autophagy via LC3-II and promote antibacterial protein (LCN2) expression, while NK cell exosomes carry perforin, granulysin, and miR-1249-3p to induce apoptosis of infected macrophages. Neutrophil microvesicles enhance macrophage activation, autophagy, and antigen presentation. DCs capture EVs-associated antigens via Siglec-1, undergo maturation, and present antigens to T cells, driving IFN-γ production and adaptive immunity; apoptotic bodies also deliver antigens to DCs via Annexin A1-mediated uptake. Additionally, endothelial cell permeability is increased by serum exosomes to facilitate immune cell recruitment, while mesenchymal stem cell exosomes deliver miR-20b to alveolar epithelial cells, inhibiting excessive inflammation through TLR2/4-NF-κB signaling suppression. Collectively, these EVs-mediated processes form a dynamic regulatory network that balances effective pathogen clearance with tissue damage limitation. Mtb: Mycobacterium tuberculosis; EVs: extracellular vesicles; Mtb EVs: Mycobacterium tuberculosis-derived extracellular vesicles; HC EVs: host cell-derived extracellular vesicles; DC: dendritic cell; TLR2/4: Toll-like receptors 2 and 4; NF-κB: nuclear factor kappa B; TNF-α: tumor necrosis factor-α; IL-6: interleukin-6; IL-1β: interleukin-1β; CCL2: C-C motif chemokine ligand 2; MCP-1: monocyte chemoattractant protein-1; RNA: ribonucleic acid; RIG-I: retinoic acid-inducible gene I; LC3-II: microtubule-associated protein 1 light chain 3-II; LCN2: lipocalin-2; NK: natural killer cell; miR: microRNA; SKOR1: SKI family transcriptional corepressor 1; Siglec-1: sialic acid-binding immunoglobulin-like lectin 1; MHC-I/II: major histocompatibility complex classes I and II; CD86: cluster of differentiation 86; IFN-γ: interferon-γ; ISG15: interferon-stimulated gene 15; MSC: mesenchymal stem cell.
