Inflammation-associated monocytes express ACOD1 to curtail inflammatory behaviour in IBD and experimental colitis

Monocytes are essential for replenishing homeostatic macrophages in the intestine. However, they also accumulate in significant numbers when intestinal homeostasis is disrupted in diseases, such as inflammatory bowel disease (IBD). The molecular pathways governing monocyte behaviour across these different contexts remain poorly understood. Here, we profile the monocyte / macrophage compartment in human IBD using single-cell RNA sequencing and identify a discrete population of monocytes that accumulate in IBD, which we term inflammation associated monocytes (IAMs). These can be identified by the expression of CD319, CD274 and CCRL2, and demonstrate increased expression of IBD susceptibility genes. By performing cross-species analysis, we show an analogous population of IAMs accumulate during chemically induced colitis in mice. Using transgenic fate mapping approaches, we show these cells likely derive from a discrete precursor in the bone marrow (BM) and are locally imprinted to produce heightened IL-1{beta} and TNF in mouse and humans. Importantly, we show that co-incident with a hyper-inflammatory phenotype, these same cells uniquely and specifically express aconitate decarboxylase (ACOD1) in response to local Toll-like receptor (TLR) and interferon (IFN) receptor signalling, to limit unrestricted cytokine production. Thus, the intestinal environment after injury instructs both inflammation and recovery specifically within a transitioning population of monocytes that are absent in health.