A beneficial environment promotes immune resilience through epigenetic regulation [scRNA-seq]

Environmental factors are often detrimental; however, certain environments enhance immune resilience. Notably, children raised on traditional farms show reduced allergies and asthma prevalence. Here, we investigated how a beneficial environment, using farm dust (FD) extract, influenced lung immune function in OVA-induced allergic inflammation. FD-exposure reduced allergic lung inflammation and increased monocyte-derived macrophage (MDM) recruitment. scRNA-seq revealed that FD-exposed MDMs had altered gene expression, including dampened Ccl8 and MHCII expression, impairing eosinophil recruitment and antigen presentation. RNA-seq and ATAC-seq confirmed FD-induced epigenetic reprogramming ex-vivo, on bone marrow-derived macrophages. This modulation, seen in both human and murine cells, relied on HDAC activity sustained by PPAR? signaling. These findings suggest that beneficial environmental exposures can reprogram immune cells and may offer a novel strategy for asthma prevention. Overall design: Farm dust (FD) was collected from 9 traditional European cow farms (EUC) in Southern Germany and Austria that did not house sheep. Dust was collected from stables by sweeping settled dust from ledges, windowsills, and other, higher shelves (at least 1 m above ground) to obtain dry airborne dust. Animals were sensitized to ovalbumin (OVA) on days 0, 7, and 14 by intraperitoneal injection of 10 µg OVA emulsified in 1.0 mg aluminum hydroxide and diluted to 200 µL with PBS. Subsequently, mice were challenged on days 26, 27 and 28 with intranasal administration of 100ug OVA. FD administration was carried out via intranasal administration of 25 µL from a 100ug/ml stock solution of FD extract on days 0, 2, 5, 7, 9, 12, 14, 16, 19, 21, 23 and 26, for a total of 12 administrations. 24h after the last challenge wit OVA, mice were deeply anesthetized in MMF, exsanguinated via the hepatic artery, and one whole lung was processed for scRNAseq.