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

Goess, M. C.; Heinze, J. M.; Hofmann, J. N.; Buck, A.; Gadjalova, I.; Weber, M.-C.; Ring, S.; Buescher, J. M.; Villa, M.; Neumann, P.-A.; Ruland, J.; Keppler, S. J.

doi:10.1101/2025.07.11.664132

bioRxiv · 10.1101/2025.07.11.664132

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

Goess, M. C.·Heinze, J. M.·Hofmann, J. N.·Buck, A.·Gadjalova, I.·Weber, M.-C.·Ring, S.·Buescher, J. M.·Villa, M.·Neumann, P.-A.·Ruland, J.·Keppler, S. J.

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Abstract

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

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Goess, M. C., Heinze, J. M., Hofmann, J. N., Buck, A., Gadjalova, I., Weber, M.-C., Ring, S., Buescher, J. M., Villa, M., Neumann, P.-A., Ruland, J., Keppler, S. J.. 2025-07-14. B cell/adipocyte crosstalk drives pro-fibrotic macrophage migration and polarisation in Crohn`s disease-associated, inflamed adipose tissue. https://doi.org/10.1101/2025.07.11.664132

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