Loss of ALK3 ameliorates acute, but aggravates chronic lung inflammation in vivo

ALK3 (BMPR1a) is a type-1-receptor of the TGF-β-receptor superfamily, which translates mostly bone morphogenetic proteins, but also TGF-β1. Previously, we could show that specific deletion of ALK3 in APCs leads to increased inflammation in the skin. Whether this effect is specific to the skin or found in other tissues as well has been unknown so far.Here, we used ALK3ΔCD11c-mice as well as pharmacological blockade of ALK3-signaling with DMH-1 to investigate the role of ALK3 in Bleomycin- and LPS-induced lung inflammations. We analysed lung inflammation via histology and studied the immune reaction via flow cytometry and single-cell-RNA-sequencing. Fitting to our results from the skin, we found that deletion or blockade of ALK3 aggravates long-lasting lung inflammations by reducing the number of TREG. Thus, ALK3 in APCs is important for dampening chronic lung inflammations. Surprisingly, we observed the opposite effect in acute inflammations: here, blockade of ALK3 ameliorated the inflammation. We found that ALK3 acts on APCs, reducing their state of activation and changing the secretion of chemokines. This in turn reduces activity of neutrophils, leading to reduced lung inflammation.Thus, ALK3 has a dual role in lung inflammations. It contributes to initiation of acute inflammation, but dampens longer-lasting inflammations. To understand the underlying mechanisms of how DMH1 partially rescue lung inflammation cased by LPS, we performed scRNA-seq to analyze gene expression in different lung cell types under 3 different conditions.