15 research outputs found
The nuclear receptor LXRα controls the functional specialization of splenic macrophages.
Macrophages are professional phagocytic cells that orchestrate innate immune responses and have considerable phenotypic diversity at different anatomical locations. However, the mechanisms that control the heterogeneity of tissue macrophages are not well characterized. Here we found that the nuclear receptor LXRα was essential for the differentiation of macrophages in the marginal zone (MZ) of the spleen. LXR-deficient mice were defective in the generation of MZ and metallophilic macrophages, which resulted in abnormal responses to blood-borne antigens. Myeloid-specific expression of LXRα or adoptive transfer of wild-type monocytes restored the MZ microenvironment in LXRα-deficient mice. Our results demonstrate that signaling via LXRα in myeloid cells is crucial for the generation of splenic MZ macrophages and identify an unprecedented role for a nuclear receptor in the generation of specialized macrophage subsets
An anti-ICAM-2 (CD102) monoclonal antibody induces immune-mediated regressions of transplanted ICAM-2-negative colon carcinomas
Monoclonal antibodies (mAbs) can mediate antitumor effects by indirect mechanisms involving antiangiogenesis and up-regulation of the cellular immune response rather than by direct tumor cell destruction. From mAbs raised by immunization of rats with transformed murine endothelial cells, a mAb (EOL4G8) was selected for its ability to eradicate a fraction of established colon carcinomas that did not express the EOL4G8-recognized antigen. The antigen was found to be ICAM-2 (CD102). Antitumor effects of EOL4G8, which required a functional T-cell compartment, were abrogated by depletion of CD8(+) cells and correlated with antitumor CTL activity, whereas only a mild inhibition of angiogenesis was observed. Interestingly, we found that EOL4G8 acting on endothelial ICAM-2 markedly enhances leukotactic factor activity-1-independent adhesion of immature dendritic cells to endothelium-an effect that is at least in part mediated by DC-SIGN (CD209)
RUNX/AML and C/EBP factors regulate CD11a integrin expression in myeloid cells through overlapping regulatory elements
The CD11a/CD18 (leukocyte functionassociated
antigen 1 [LFA-1]) integrin mediates
critical leukocyte adhesive interactions
during immune and inflammatory
responses. The CD11a promoter directs
CD11a/CD18 integrin expression, and its
activity in lymphoid cells depends on a
functional RUNX1/AML-1–binding site
(AML-110) within the MS7 sequence. We
now report that MS7 contains a C/EBPbinding
site (C/EBP-100), which overlaps
with AML-110 and is bound by C/EBP
factors in myeloid cells. C/EBP and RUNX/
AML factors compete for binding to their
respective cognate elements and bind to
the CD11a promoter MS7 sequence in a
cell lineage- and differentiation-dependent
manner. In myeloid cells MS7 is
primarily recognized by C/EBP factors in
proliferating cells whereas RUNX/AMLfactors
(especially RUNX3/AML-2) bind to
MS7 in differentiated cells. RUNX3/AML-2
binding to the CD11a promoter correlates
with increased RUNX3/AML-2 protein levels
and enhanced CD11a/CD18 cell surface
expression. The relevance of the
AML-110 element is underscored by the
ability of AML-1/ETO to inhibit CD11a promoter
activity, thus explaining the low
CD11a/CD18 expression in t(8;21)–containing
myeloid leukemia cells. Therefore,
the expression of the CD11a/CD18
integrin in myeloid cells is determined
through the differential occupancy of the
CD11a proximal promoter by transcription
factors implicated in the pathogenesis
of myeloid leukemia
MMP-12, Secreted by Pro-Inflammatory Macrophages, Targets Endoglin in Human Macrophages and Endothelial Cells
Upon inflammation, monocyte-derived macrophages (MF) infiltrate blood vessels to
regulate several processes involved in vascular pathophysiology. However, little is known about
the mediators involved. Macrophage polarization is crucial for a fast and e cient initial response
(GM-MF) and a good resolution (M-MF) of the inflammatory process. The functional activity of
polarized MF is exerted mainly through their secretome, which can target other cell types, including
endothelial cells. Endoglin (CD105) is a cell surface receptor expressed by endothelial cells and MF
that is markedly upregulated in inflammation and critically involved in angiogenesis. In addition, a
soluble form of endoglin with anti-angiogenic activity has been described in inflammation-associated
pathologies. The aim of this work was to identify components of the MF secretome involved in
the shedding of soluble endoglin. We find that the GM-MF secretome contains metalloprotease 12
(MMP-12), a GM-MF specific marker that may account for the anti-angiogenic activity of the GM-MF
secretome. Cell surface endoglin is present in both GM-MF and M-MF, but soluble endoglin is
only detected in GM-MF culture supernatants. Moreover, MMP-12 is responsible for the shedding
of soluble endoglin in vitro and in vivo by targeting membrane-bound endoglin in both MF and
endothelial cells. These data demonstrate a direct correlation between GM-MF polarization, MMP-12,
and soluble endoglin expression and function. By targeting endothelial cells, MMP-12 may represent
a novel mediator involved in vascular homeostasis.Ministerio de Ciencia, Innovación y Universidades of Spain
(SAF2013-43421-R to C.B.; SAF2017-83785-R and SAF2014-23801 to A.L.C.)Consejo Superior de Investigaciones
Cientificas (201920E022 to C.B.)Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER;
ISCIII-CB06/07/0038 to C.B.)Czech Republic Specific University Research (SVV-260414 to P.N.)CIBERER is
an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain supported by FEDER fundsM.A. was funded
with a fellowship from Ministerio de Ciencia e Innovación (BES-2008-003888)M.V. was supported by a short-term
mobility fellowship from the European Erasmus Programm