Colchicine dismantles the AIM2-microtubule-NETosis axis driving thrombosis while tocilizumab removes the IL-6 fitness...
IF a combination of colchicine (0.5 mg twice daily, oral) and tocilizumab (8 mg/kg IV every 4 weeks, or equivalent subcutaneous anti-IL-6R dosing) is administered to aged (≥18-month) Jak2 V617F knock-in mice (or equivalent C57BL/6 chimeric bone marrow transplant models with ≥20% Jak2 V617F VAF), beginning after clonal dominance is established (not prophylactically),
THEN a significant reduction in JAK2 V617F variant allele frequency (VAF; target: ≥30% reduction from baseline over 16 weeks), a normalization of plasma citrullinated histone H3 (NET biomarker), a reduction in AIM2-ASC speck formation in circulating neutrophils, and a decrease in serum IL-6 and IL-1β will be observed — measurable by ddPCR for VAF, immunofluorescence for ASC specks, and multiplex cytokine profiling — compared to vehicle or monotherapy controls,
BECAUSE the following mechanistic chain connects established clonal damage to its repair:
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JAK2 V617F constitutively activates JAK-STAT signaling, generating chronic replication stress and cytosolic DNA accumulation in myeloid cells, which primes AIM2 inflammasome assembly via cytosolic DNA sensing — a pathway distinct from NLRP3 and not addressed by current cardiovascular standards of care (JAK2 V617F drives 12-fold increased ischemic risk via this mechanism, as established by Jaiswal et al. and Wolach et al., referenced throughout the Evidence Set literature review).
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AIM2 inflammasome activation requires microtubule-mediated transport of the adaptor ASC to centrosomal assembly points to form the functional "speck" complex that activates caspase-1; colchicine, by binding tubulin and disrupting microtubule polymerization, physically prevents this centrosome-directed ASC oligomerization, collapsing the AIM2-to-caspase-1-to-gasdermin-D signaling axis at its structural foundation (Misawa et al., Nature Immunology 2013, referenced in the Evidence Set).
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Downstream of AIM2 activation, caspase-1 cleaves gasdermin D and triggers NETosis — the explosive release of chromatin-histone scaffolds that drives platelet capture and thrombus formation; colchicine's concurrent disruption of actin-cytoskeletal rearrangement and chromatin decondensation further impairs NETosis at a second mechanistic node independent of inflammasome assembly, as JAK2 was shown to modulate neutrophil function via plasma membrane composition and actin cytoskeletal dynamics (JAK2 promotes neutrophil migration and NETosis via effects on plasma membrane composition and actin cytoskeletal organization)[https://doi.org/10.1101/2025.04.21.649782].
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Caspase-1 activation simultaneously processes pro-IL-1β to mature IL-1β, which is released into the local hematopoietic niche; IL-1β then drives hepatic and stromal IL-6 production, creating a cytokine amplification loop. Serum amyloid A (SAA), elevated chronically in aging and cardiovascular disease, further amplifies this loop by acting as a two-signal priming agent — upregulating pro-IL-1β transcripti...
SENS category: OncoSENS
Key references: • doi.org/10.1101/2025.04.21.649782]. • doi.org/10.1371/journal.pone.0096703]. • doi.org/10.1101/2025.06.23.25330105], • doi.org/10.1101/2024.06.15.24308845], • doi.org/10.1101/2025.06.23.25330105].