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

During Crohns 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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/664132v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@15de8f9org.highwire.dtl.DTLVardef@6a6873org.highwire.dtl.DTLVardef@1ef7a22org.highwire.dtl.DTLVardef@13b89a4_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryO_LIB cells and pro-fibrotic macrophages accumulate in IBD-associated, inflamed adipose tissue C_LIO_LIB cell depletion in a mouse model reduces pro-fibrotic macrophage accumulation in IBD-associated, inflamed adipose tissue C_LIO_LIB cell/adipocyte crosstalk promotes B cell activation and MCP-1 secretion by adipocytes C_LIO_LIAdipocyte-derived MCP-1 promotes migration of macrophages C_LIO_LIB cell/adipocyte crosstalk provides a lactate-rich, inflammatory environment which likely drives pro-fibrotic macrophage polarisation C_LI