Monocytes are a heterogeneous population of phagocytic cells that are generated in the bone marrow and released into the bloodstream. There are two main monocyte subsets in mice: “inflammatory” monocytes that are Ly6Chi CCR2hi CX3 CR1low and “alternative” or “patrolling” monocytes that are Ly6Clow CCR2low CX3 CR1hi. The process of monocyte recruitment and differentiation is still a matter of controversy. In this issue, Dal-Secco et al. report in situ monocyte reprogramming in the liver, from proinflammatory CCR2hi CX3 CR1low cells into reparative CCR2low CX3 CR1hi cells and show, for the first time, that this occurs at the site of injury.Fil: Quintar, Amado Alfredo. la Jolla Institute For Allergy And Immunology; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Hedrick, Catherine C. . la Jolla Institute For Allergy And Immunology; Estados UnidosFil: Ley, Klaus. la Jolla Institute For Allergy And Immunology; Estados Unido

Amado A. Quintar

Catherine C. Hedrick

Dal-Secco

Klaus Ley

The Journal of Experimental Medicine

PubMed

Quintar, Amado Alfredo

Hedrick, Catherine C.

Ley, Klaus

LAReferencia - Red Federada de Repositorios Institucionales de Publicaciones Científicas Latinoamericanas

INSIGHTS432 INSIGHTS | The Journal of Experimental MedicineMonocytes are a heterogeneous population of phagocytic cells that are generated in the bone marrow and released into the bloodstream. There are two main monocyte subsets in mice: “inflammatory” monocytes that are Ly6Chi CCR2hi CX3CR1low and “alternative” or “patrolling” monocytes that are Ly6Clow CCR2low CX3CR1hi. The process of monocyte recruitment and differentiation is still a matter of controversy. In this issue, Dal-Secco et al. report in situ monocyte reprogramming in the liver, from proinflammatory CCR2hi CX3CR1low cells into reparative CCR2low CX3CR1hi cells and show, for the first time, that this occurs at the site of injury.Dal-Secco et al. harnessed the power of imaging technology and fluorescent re-porter mice to track monocytes in a model of sterile inflammation in the liver (induced after a 30 µm3 burn by a thermal probe). In this model, the recruitment of monocytes is dependent on CCR2 present on CCR2hi CX3CR1low monocytes. Some of these cells were observed patrolling the liver sinusoids in the steady state. Within 24–48 hours, CCR2hi CX3CR1low monocytes extra-vasated and formed a ring structure surrounding the necrotic tissue at the site of the injury. These extravascular monocytes started to differentiate and, by 48–72 hours, had lost CCR2 expression and gained CX3CR1 and MHC class II expression (CCR2low CX3CR1hi CD11bhi MHCIIhi CD64hi F4/80-). Blocking IL-10 and IL-4 delayed this phenotypic transition and impaired wound healing as shown by failure to clear necrotic hepatocytes and failure to deposit collagen.These findings reveal a mechanism for monocyte transformation in situ in response to sterile inflammation in the liver, starting with the abundant pool of circulating Ly6Chi CCR2hi CX3CR1low monocytes and exploiting their plasticity for on-site education and conversion. Monocyte conversion from inflammatory to alternative phenotypes has previously been shown to occur in the bone marrow, but this paper shows that phenotypic conversion can also occur in the liver. The dependence on IL-4 and IL-10 for this phenotypic switch is reminiscent of alternatively activated macrophages, similar to wound-healing M2 cells. Further work will be required to investigate the hepatic source of IL-4 and IL-10 and determine how these cytokines induce phenotypic conversion. Investigations that address the nature and source of the CCR2 ligands that recruit inflammatory monocytes to sites of sterile injuries and of the chemokine(s) that facilitate entry of CX3CR1hi monocytes into necrotic lesions may also provide fascinating answers.These results provide new data on the plasticity of monocytes in the tissue microenvironment which may lead to new oppor-tunities for therapeutic intervention in disease.Dal-Secco, D., et al. 2015. J. Exp. Med. http://dx.doi.org/10.1084/jem.20141539.Monocyte phenotypes: When local education countsInsight from (left to right) Amado Quintar, Catherine Hedrick, and Klaus LeyA focal sterile injury induces the recruitment of CCR2hi monocytes (red) to the liver, which form a ring surround-ing and "walling off" the necrotic lesion. After 48–72 hours, monocytes start to gain CX3CR1 expression (orange) and undergo an IL-4/IL-10–mediated phenotypic conver-sion into CCR2low CX3CR1hi CD11bhi MHCIIhi CD64hi F4/80- monocytes (green). These cells infiltrate the necrotic tissue and induce collagen deposi-tion leading to the clearance of dead cells.Amado A. Quintar, Catherine C. Hedrick, and Klaus Ley,  La Jolla Institute for Allergy & Immunology: klaus@liai.orgThe Journal of Experimental Medicine on April 7, 2015jem.rupress.orgDownloaded from Published April 6, 2015JEM Vol. 212, No. 4 433Allergic reactions arise when people become sensitized to otherwise harmless environmental antigens. In this issue, Shade et al. reveal that the immunoglobulin  (IgE) antibodies that mediate these reactions have a key vulnerability. They report that the ability of IgE to trigger an allergic reaction through its interaction with mast cells is dependent on a single site of antibody glycosylation. With the in vivo targeting of specific glycoprotein glycans emerging as a viable strategy for modulating endogenous glycoprotein function, these findings are of significant interest.IgE is found tightly bound to mast cells through the interaction with the high-affinity Fc receptor (FcRI). This interaction is sufficiently tight that IgE antibodies are stably immobilized on the immune cells, sensitizing them to specific antigens for extended periods of time. The IgE–FcRI interaction occurs through the IgE Fc domain. Glycosylation of antibody Fc domains has been known to be important in the interaction of IgG with cel-lular Fcg receptors, but there has been conflicting evidence on the role of the equivalent IgE Fc glycans. Shade et al. show that glycosylation of IgE is essential for both FcRI binding and the triggering of mast cell degranulation. Using a panel of mutants, they demonstrate that IgE effector function is dependent on the glycan at a single glycosylation site in the C3 domain at Asn394 and Asn384 in human and mouse IgE, respectively.Typically mammalian glycans are efficiently processed during glycoprotein folding and secretion from the oligomannose-type glycans added cotranslationally to a highly heterogeneous mix of complex-type glycans. The C3 glycosylation site identi-fied to be critical for receptor binding has been shown by Shade and others to be trapped in the oligomannose state. Examination of the previously reported crystal structure reveals that these glycans are located in the interstitial space between opposing C3 of the homodimeric IgE Fc. The efficient processing to complex glycans is likely to be limited by either the extensive glycan–protein interactions or by steric blocking of the processing enzymes by the wider proteinous environment. Importantly, Shade et al. suggest that the unusual presence of oligomannose glycans at this critical site offers an opportunity to specifically target this structure to shut down the allergic response. They show that a bacterial endoglycosidase from Flavobacterium meningosepticum (EndoF1) that specifically hydrolyses oligomannose-type glycans can disrupt IgE effector functions. Whether bacterial enzymes can ever be used clinically is a point of some debate. Despite their ability to turn off elements of the immune response, it is likely that the immunogenicity of bacterial enzymes will limit any clinical applications to a single dose. The IgG-degrading enzyme from Streptococcus pyogenes, IdeS, is being investigated as a single-dose treatment to enable kidney transplantation for patients who have antibodies that target prospective kidneys and, encouragingly, has recently been shown to be well tolerated in humans in a small-scale safety trial.These clinical considerations aside, this study demonstrates the importance of IgE glycosylation in allergic responses and provides a route to the selective disruption of this mechanism in allergic diseases.Shade, K.-T.C., et al. 2015. J. Exp. Med. http://dx.doi.org/10.1084/jem.20142182.(A and B) Molecular model of the glycosylated IgE Fc domain. The IgE Fc glycans are shown as sticks with surface representation. (C) The structure of panel A is illustrated schematically and the glycans are colored throughout according to their requirement for FcRI-mediated immune response. Molecular model courtesy of Dr. Mark Wormald.Max Crispin, Oxford Glycobiology Institute, University of Oxford: max.crispin@bioch.ox.ac.ukBreaking the allerg ic response by disrupting  antibody glycosylationInsight from Max Crispin on April 7, 2015jem.rupress.orgDownloaded from Published April 6, 2015

Monocyte phenotypes: when local education counts

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