Arunachalam, A. | bioRxiv Science

bioRxiv2026

Interstitial macrophages drive chronic lung allograft dysfunction

Despite immunosuppressive regimens targeting adaptive immunity, chronic lung allograft dysfunction (CLAD) remains the major obstacle to durable lung allograft survival. Here, we identify colony-stimulating factor 1 receptor (CSF1R)-expressing interstitial macrophages as critical orchestrators of CLAD. Using lung tissue from patients with CLAD and a mouse model of mismatched lung transplantation, we show that both donor-derived tissue-resident and recipient- monocyte-derived interstitial macrophages spatially co-localize within peribronchial immune aggregates in patients with CLAD. These interstitial macrophages express distinct cytokine programs that include those implicated in the recruitment of T and B cells. Pharmacological inhibition of CSF1R after lung transplantation in mice reduced interstitial macrophage abundance and attenuated CLAD pathology. Our findings identify donor- and recipient-derived interstitial macrophages as upstream regulators of CLAD and suggest CSF1R as a therapeutic target for its prevention and treatment.

immunology↗

bioRxiv2024

Resolving atomic-level dynamics and interactions of high-molecular weight hyaluronic acid in biomimetic ECM hydrogels by multidimensional solid-state NMR

High molecular weight (HMW) hyaluronic acid (HA) is a highly abundant natural polysaccharide and a fundamental component of the extracellular matrix (ECM). Its size and concentration regulate tissues macro- and microenvironments, and its upregulation is a hallmark feature of certain tumors. Yet, the conformational dynamics of HMW-HA and how it engages with components of the ECM microenvironment remain poorly understood on the molecular level. Probing the molecular structure and dynamics of HMW polysaccharides in a hydrated, physiological-like environment is crucial but also technically challenging. Here, we deploy advanced magic-angle-spinning (MAS) solid-state NMR (ssNMR) spectroscopy in combination with isotopic enrichment to enable an in-depth study of HMW-HA to address this challenge. This approach resolves multiple coexisting HA conformations and dynamics as a function of environmental conditions. By combining 13C-labeled HA with unlabeled ECM components, we detect by MAS NMR HA-specific changes in global and local conformational dynamics as a consequence of hydration and ECM interactions. These measurements reveal atom-specific variations in dynamics and structure of the N-acetylglucosamine (GlcNAc) moiety of HA. We discuss possible implications for interactions that stabilize the structure of HMW-HA and facilitate its recognition by HA-binding proteins. The described methods apply similarly to studies of the molecular structure and dynamics of HA in tumor contexts and in other biological tissues, as well as HMW-HA hydrogels and nanoparticles used for biomedical and/or pharmaceutical applications.

biophysics↗