Biology subjects

Heinze, J. M.

Publications and source records attributed to Heinze, J. M..

3 recordsLinked to original sources

bioRxiv2025

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

immunology↗

bioRxiv2022

B/T cell crosstalk and aberrant inflammatory IgG exacerbate autoimmune intestinal inflammation

Dysregulated B cell responses have been described in inflammatory-bowel disease (IBD) patients; however, the role of B cells in IBD pathology remained incompletely understood. We here described Wiskott-Aldrich Syndrome interacting protein deficient (Wipf1-/-) mice as novel mouse model of spontaneous, chronic colitis modelling human IBD. Concomitant with aberrant IgG production in colonic tissue of Wipf1-/- mice, we identified systemic, hypo-sialylated IgG as drivers of IL-1{beta} production in monocytes. Pathological antibody production was promoted by the hyper-reactivity of Wipf1-/- B cells in response to LPS stimulation, resulting in efficient activation of the MAPK/Erk and mTOR/Akt/4E-BP1 pathways and heightened metabolic activity. In addition to abundant inflammatory IgG, we found that B cells directly promoted the production of pro-inflammatory cytokines by intestinal CD4+ T cells. B/T co-culture assays defined the co-stimulatory molecule CD86 as driver of IFN-{gamma} and GM-CSF production by CD4+ T cells. CD86 expression was further enhanced by the presence of sCD40L, which was elevated in sera of Wipf1-/- mice. Similarly, colonic B cells of IBD patients expressed increased mRNA levels of CD86 correlating with enhanced levels of systemic sCD40L. Together, B cell-mediated pro-inflammatory cytokine secretion and B cell-derived inflammatory antibody production contributed to exacerbated pathogenesis during intestinal inflammation. O_FIG O_LINKSMALLFIG WIDTH=168 HEIGHT=200 SRC="FIGDIR/small/507066v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1449ae8org.highwire.dtl.DTLVardef@116045borg.highwire.dtl.DTLVardef@77f3f2org.highwire.dtl.DTLVardef@130a271_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryB cells fuel intestinal inflammation

immunology↗

bioRxiv2020

APEX-based proximity labeling in Plasmodium identifies a membrane protein with dual functions during mosquito infection

Transmission of the malaria parasite Plasmodium to mosquitoes necessitates gamete egress from red blood cells to allow zygote formation and ookinete motility to enable penetration of the midgut epithelium. Both processes are dependent on the secretion of proteins from distinct sets of specialized vesicles. Inhibiting some of these proteins has shown potential for blocking parasite transmission to the mosquito. To identify new transmission blocking vaccine candidates, we defined the microneme content from ookinetes of the rodent model organism Plasmodium berghei using APEX2-mediated rapid proximity-dependent biotinylation. Besides known proteins of ookinete micronemes, this identified over 50 novel candidates and sharpened the list of a previous survey based on subcellular fractionation. Functional analysis of a first candidate uncovered a dual role for this membrane protein in male gametogenesis and ookinete midgut traversal. Mutation of a putative trafficking motif in the C-terminus led to its mis-localization in ookinetes and affected ookinete to oocyst transition but not gamete formation. This suggests the existence of distinct functional and transport requirements for Plasmodium proteins in different parasite stages. SignificanceThe genome of the malaria parasite Plasmodium contains over 5500 genes, of which over 30% have no assigned function. Transmission of Plasmodium spp. to the mosquito contains several essential steps that can be inhibited by antibodies or chemical compounds. Yet few proteins involved in these processes are characterized, thus limiting our capacity to generate transmission interfering tools. Here, we establish a method to rapidly identify proteins in a specific compartment within the parasite that is essential for establishment of an infection within the mosquito, and identify over 50 novel candidate proteins. Functional analysis of the top candidate identifies a protein with two independent essential functions in subsequent steps along the Plasmodium life cycle within the mosquito. HighlightsO_LIfirst use of APEX based proximity ligation in Apicomplexa C_LIO_LIidentification of >50 putative ookinete surface proteins C_LIO_LInovel membrane protein essential for microgamete egress and ookinete migration C_LIO_LIputative trafficking motif essential in ookinetes but not gametes C_LI

cell biology↗