Matthias Nahrendorf

The skull bone marrow (SBM) is emerging as a critical hub for neuroimmune signaling, yet its role in chronic pain is unknown. Using integrated positron emission tomography/magnetic resonance imaging, here, we show that the levels of 18-kilodalton translocator protein (TSPO), a putative marker of immune cell density, are elevated in the SBM of individuals with chronic pain [ n = 125; chronic low back pain (cLBP), n = 88; knee osteoarthritis (KOA), n = 37] compared with healthy controls ( n = 22). These elevations were widespread, generally more pronounced for KOA than cLBP, associated with pain and pain-comorbid symptoms in partially segregated spatial patterns, and supported by preliminary immunohistochemical evidence in human SBM samples from a donor with a history of chronic pain (compared with a healthy donor). Because TSPO is highly expressed in myeloid cells, these results link SBM immune dysregulation with chronic pain and its associated psychological and functional impairments. These findings provide a strong rationale for investigating this previously overlooked structure, which remains largely underexplored in the context of pain.

Hydrogels that adhere to biological tissues and resist fibrosis are required to provide both optimal functionality and appropriate stiffness on diverse soft tissues to achieve therapeutic efficacy and biocompatibility. However, their performance is often limited by an intrinsic trade-off between functionality and stiffness. Through the incorporation of polymer brush coatings, we develop a modular hydrogel system to enable independent control of functionality and stiffness. By tailoring coating chemistry, coating thickness, and hydrogel network topology, we obtain consistent bioadhesion (~100 joules per square meter) and fibrosis suppression across the full stiffness range of soft tissues (1 kilopascal to 1 megapascal). Using this approach, we design a hydrogel that can maintain stable adhesion in vivo on a beating mouse heart and a hydrogel with no fibrotic capsule in immunocompetent mice over 40 days. This modular system offers a customizable approach for designing functional implants with tailored mechanical properties.

Atrial fibrillation and the risk of its lethal complications are propelled by fibrosis, which induces electrical heterogeneity and gives rise to reentry circuits. Atrial TREM2⁺ macrophages secrete osteopontin (encoded by Spp1), a matricellular signaling protein that engenders fibrosis, inflammation, and atrial fibrillation. Here we developed an antibody–siRNA conjugate (ARC) drug candidate to silence Spp1. The ARC relies on an anti-TREM2 antibody for delivering Spp1-targeted siRNA to a pathogenic macrophage subset that expands in human atrial fibrillation. The ARC preferentially targeted atrial TREM2⁺ macrophages with limited uptake by other immune or stromal cells of the heart. We observed efficient silencing of the target gene in human myocardium and in mice, where it reduced pro-fibrotic fibroblast activation and atrial fibrosis. Four weeks of systemic ARC treatment suppressed inducible atrial fibrillation in mice exposed to clinically prevalent risk factors. These results suggest that macrophage subset targeting offers a viable immunomodulatory strategy for atrial fibrillation.

BACKGROUND: Monocytes contribute to the initiation and propagation of venous thrombosis. Little is known about the roles monocytes play in arterial thrombosis, the cause of stroke and myocardial infarction. METHODS: We investigated how CCR2 (CC chemokine receptor 2) knockout ( ^−/− )-mediated monocyte deficiency affects platelet function, blood coagulation, thrombus volume, and thrombolytic susceptibility in 666 male mice with FeCl ₃ -mediated carotid arterial thrombosis, including 365 C57BL/6 wild type (WT) mice, 295 CCR2 ^−/− mice, and 6 CX3CR1-GFP (CX3C chemokine receptor 1–green fluorescent protein) mice. RESULTS: Intravital microscopy and flow cytometry showed that both neutrophils and monocytes were recruited to the acute arterial thrombus, as observed 30 minutes post-thrombosis. Platelet function tests demonstrated platelet aggregation to be lower in the whole blood of CCR2 ^{− /−} mice (versus C57BL/6 WT mice) but not in their leukocyte-free platelet-rich plasma, suggesting this platelet dysfunction is cell-mediated. Flow cytometry experiments revealed lower numbers of monocyte–platelet aggregates in the blood of CCR2 ^{− /−} mice, compared with C57BL/6 WT mice. Blood levels of FXIII (factor XIII) and monocyte levels of FXIII-A were increased after carotid thrombosis in C57BL/6 WT mice but not CCR2 ^{− /−} mice. Further, in vivo micro-computed tomography-based thrombus imaging using fibrin-targeted gold nanoparticles and histology showed that CCR2 ^{− /−} mice had smaller thrombi (0.112±0.002 mm ³ , n=22) than C57BL/6 WT mice (0.125±0.007 mm ³ , n=27; P − ^/− mice and CCR2-siRNA-treated mice, compared with C57BL/6 WT mice. In addition, clopidogrel reduced baseline thrombus volume more, but CCR2 ^{− /−} better facilitated tPA-mediated thrombolysis. CONCLUSIONS: CCR2 antagonism decreases platelet aggregation and reduces FXIII levels in blood and monocytes, thus driving arterial thrombosis towards the generation of a relatively small, porous, more lysable clot.