B cell/adipocyte crosstalk drives pro-fibrotic macrophage migration and polarisation in Crohn’s disease-associated, inflamed adipose tissue

During Crohn’s disease (CD), hyperplasia of the mesenteric white adipose tissue (WAT), called creeping fat (CrF), is associated with the accumulation of immune cells. We here investigated whether B cell infiltration and their interaction with adipocytes influence inflammation and fibrosis of CD-associated adipose tissue. Analysing CrF of CD patients as well as WAT from a mouse model of intestinal inflammation, we found an accumulation of B cells and pro-fibrotic, M2-like macrophages. Depleting B cells through anti-CD20 antibody treatment diminished M2-like macrophage accumulation in inflamed mouse WAT. Mechanistically, we found that the B cell/adipocyte co-cultures led to elevated secretion of monocyte chemoattractant protein-1 (MCP-1) by primary adipocytes, in part due to TNF-a secretion by activated B cells. Adipocyte-derived MCP-1 resulted in enhanced macrophage migration. Furthermore, the supernatants of the B cell/adipocyte co-culture promoted pro-fibrotic, M2-like macrophage polarization in vitro , correlating with elevated levels of lactate. Single-cell RNA sequencing of human CrF and mouse WAT supported our in vitro findings suggesting that the B cell/adipocyte crosstalk supports a lactate-rich, inflammatory adipose tissue niche. Taken together, our results provide evidence for a crucial role of the B cell/adipocyte crosstalk to CD-associated adipose tissue inflammation.