TY - JOUR
T1 - β7 integrins are required to give rise to intestinal mononuclear phagocytes with tolerogenic potential
AU - Villablanca, Eduardo J.
AU - De Calisto, Jaime
AU - Paredes, Patricia Torregrosa
AU - Cassani, Barbara
AU - Nguyen, Deanna D.
AU - Gabrielsson, Susanne
AU - Mora, J. Rodrigo
PY - 2014
Y1 - 2014
N2 - Background and objective: While pro-inflammatory monocyte trafficking to the intestine has been partially characterised, the molecules required for migration of tolerogenic mononuclear phagocytes (dendritic cells (DC) and macrophages) are unknown. We hypothesised that the gut-homing receptor integrin α4β7 is required for this process. Methods: We used a T cell-mediated colitis model to study the role of α4β7 in the innate immune compartment. We then performed competitive bone marrow (BM) reconstitution experiments to assess the requirement of α4β7 in the generation of intestinal retinoic acid (RA)-producing CD11chi DC (ALDE+DC) and CD64 macrophages. Using mixed BM chimeras we also asked whether α4β7 is required to give rise to tolerogenic mononuclear phagocytes. Results: Lack of β7 integrins in the innate immune compartment (β7-/-RAG2-/-mice) markedly accelerated T cell-mediated colitis, which was correlated with lower numbers and frequencies of ALDE+DC in mesenteric lymph nodes. Consistent with a role of α4β7 in the generation of intestinal mononuclear phagocytes, BM cells from β7-/-mice poorly reconstituted small intestine ALDE +DC and MΦ when compared to their wild type counterparts. In addition, mice lacking β7 integrins in the CD11chi compartment showed decreased ability to induce Foxp3+ TREG and IL-10-producing T cells. Conclusions Mice lacking β7 integrins in the innate immune compartment are more susceptible to intestinal inflammation, which is correlated with a requirement of β7 integrins to reconstitute gut mononuclear phagocytes with tolerogenic potential.
AB - Background and objective: While pro-inflammatory monocyte trafficking to the intestine has been partially characterised, the molecules required for migration of tolerogenic mononuclear phagocytes (dendritic cells (DC) and macrophages) are unknown. We hypothesised that the gut-homing receptor integrin α4β7 is required for this process. Methods: We used a T cell-mediated colitis model to study the role of α4β7 in the innate immune compartment. We then performed competitive bone marrow (BM) reconstitution experiments to assess the requirement of α4β7 in the generation of intestinal retinoic acid (RA)-producing CD11chi DC (ALDE+DC) and CD64 macrophages. Using mixed BM chimeras we also asked whether α4β7 is required to give rise to tolerogenic mononuclear phagocytes. Results: Lack of β7 integrins in the innate immune compartment (β7-/-RAG2-/-mice) markedly accelerated T cell-mediated colitis, which was correlated with lower numbers and frequencies of ALDE+DC in mesenteric lymph nodes. Consistent with a role of α4β7 in the generation of intestinal mononuclear phagocytes, BM cells from β7-/-mice poorly reconstituted small intestine ALDE +DC and MΦ when compared to their wild type counterparts. In addition, mice lacking β7 integrins in the CD11chi compartment showed decreased ability to induce Foxp3+ TREG and IL-10-producing T cells. Conclusions Mice lacking β7 integrins in the innate immune compartment are more susceptible to intestinal inflammation, which is correlated with a requirement of β7 integrins to reconstitute gut mononuclear phagocytes with tolerogenic potential.
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U2 - 10.1136/gutjnl-2013-305386
DO - 10.1136/gutjnl-2013-305386
M3 - Article
C2 - 24030488
AN - SCOPUS:84905594747
VL - 63
SP - 1431
EP - 1440
JO - Gut
JF - Gut
SN - 0017-5749
IS - 9
ER -