Inflammation and tissue regeneration follow tissue damage, but little is known about how these processes are coordinated. Tirone et al. show that alternative redox forms of high mobility group box 1 (HMGB1), the “alarmin” signal released by damaged cells, trigger inflammation or tissue repair after injury by interacting with distinct receptors and that a nonoxidizable HMGB1 mutant promotes regeneration without exacerbating inflammation.

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Colorectal cancer (CRC) metastatic dissemination to the liver is one of the most life‐threatening malignancies in humans and represents the leading cause of CRC‐related mortality. Herein, we adopted a gene transfer strategy into mouse hematopoietic stem/progenitor cells to generate immune‐competent mice in which TEMs—a subset of Tie2+ monocytes/macrophages found at peritumoral sites—express interferon‐alpha (IFNα), a pleiotropic cytokine with anti‐tumor effects. Utilizing this strategy in mouse models of CRC liver metastasis, we show that TEMs accumulate in the proximity of hepatic metastatic areas and that TEM‐mediated delivery of IFNα inhibits tumor growth when administered prior to metastasis challenge as well as on established hepatic lesions, improving overall survival. Further analyses unveiled that local delivery of IFNα does not inhibit homing but limits the early phases of hepatic CRC cell expansion by acting on the radio‐resistant hepatic microenvironment. TEM‐mediated IFNα expression was not associated with systemic side effects, hematopoietic toxicity, or inability to respond to a virus challenge. Along with the notion that TEMs were detected in the proximity of CRC metastases in human livers, these results raise the possibility to employ similar gene/cell therapies as tumor site‐specific drug‐delivery strategies in patients with CRC.

SummarySystemic lupus erythematosus is an autoimmune disorder characterized by increased levels of lymphocyte activation, antigen presentation by dendritic cells, and the formation of autoantibodies. This leads to immune complex-mediated glomerulonephritis. Toll-like receptor 7 (T7) and TLR9 localize to the endosomal compartment and play important roles in the generation of autoantibodies against nuclear components, as they recognize RNA and DNA, respectively. In contrast, very little is known about endogenous TLR8 activation in mice. We therefore tested whether TLR8 could affect autoimmune responses in a murine model of lupus. We introduced a Tlr8 null mutation into C57BL/6 mice congenic for the Nba2 (NZB autoimmunity 2) locus and bearing the Yaa (Y-linked autoimmune acceleration) mutation containing a tlr8 duplicated gene, and monitored disease development, autoantibody production, and glomerulonephritis-associated mortality. Cellular responses were investigated in female Nba2.TLR8 À/À mice bearing no copy of tlr8. The TLR8 deficiency accelerated disease progression and mortality, increased the number of circulating antibodies and activated monocytes, and heightened cellular responses to TLR7 ligation. TLR8-deficient antigen-presenting cells exhibited increased levels of MHC class II expression. The ability of dendritic cells to present antigens to allogeneic T cells after TLR7 ligation was also improved by TLR8 deficiency. TLR8 deletion accelerated autoimmunity in lupus-prone mice in response to TLR7 activation. Antigen-presenting cell function seemed to play a key role in mediating the effects of TLR8 deficiency.

SLE pathogenesis is complex, but it is now widely accepted that autoantibodies play a key role in the process by forming excessive immune complexes; their deposits within tissues leading to inflammation and functional damages. A proliferation inducing ligand (APRIL) is a member of the tumor necrosis factor (TNF) superfamily mediating antibody-producing plasma cell (PC)-survival that may be involved in the duration of pathogenic autoantibodies in lupus. We found significant increases of APRIL at the mRNA and protein levels in bone marrow but not spleen cells from NZB/W lupus mice, as compared to control mice. Selective antibody-mediated APRIL blockade delays disease development in this model by preventing proteinuria, kidney lesions, and mortality. Notably, this was achieved by decreasing anti-DNA and anti-chromatin autoantibody levels, without any perturbation of B- and T- cell homeostasis. Thus, anti-APRIL treatment may constitute an alternative therapy in SLE highly specific to PCs compared to other B-cell targeting therapies tested in this disease, and likely to be associated with less adverse effects than any anti-inflammatory and immunosuppressant agents previously used.

The innate Toll-like receptor 7 (TLR7) detects infections by recognizing viral and bacterial single-stranded RNA. In addition to pathogen-derived RNA, immune cells expressing high levels of TLR7, such as B cells and dendritic cells (DCs), can be activated by self-RNA. During myelin-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, TLR7 expression is increased within the central nervous system (CNS). To define the contribution of TLR7 to the development of EAE, we evaluated the course of the disease in C57BL/6-Tlr7-deficient mice compared with that in WT mice and found that TLR7-deficient mice had decreased disease severity. This protection was associated with decreased myelin oligodendrocyte glycoprotein-specific T-cell activation by primed DCs, decreased circulating autoantibodies, attenuated inflammation within the CNS, and increased Foxp3 + regulatory T cells in the periphery and in the CNS. In conclusion, we show that TLR7 is involved in the maintenance of autoimmunity in the pathogenesis of EAE.Keywords: EAE r IL-10 r Multiple sclerosis r TLR7 r Treg cell IntroductionRecognition of microbial components by Toll-like receptors (TLRs) is crucial for host responses against pathogens. While most TLRs are expressed on the cell surface, others such as TLR3, -7, -8, and -9 are expressed intracellularly within endosomal compartments where they detect nucleic acids. Endosomal TLRs recognize viral double-stranded RNA (TLR3), unmethylated CpG DNA Correspondence: Dr. Marie-Laure Santiago-Raber e-mail: marie.santiago@unige.ch (TLR9), and viral single-stranded RNA or synthetic compounds such as imidazoquinolines (TLR7/TLR8) (as reviewed by Kawai and Akira [1]). Previous studies have further provided evidence for the involvement of TLR signaling in the induction of autoantibodies [2,3]. Others studies have implicated TLR7 gene duplication in the pathogenesis of autoimmune diseases such as lupus [4,5]. TLR7 is mainly expressed by B cells but also by dendritic cells (DCs), principally plasmacytoid DCs (pDCs). B cells and pDCs appear to have developed specialized mechanisms for enhancing the delivery of potential ligands to TLR7-and TLR9-containing compartments [6]. In view of the pivotal role of (i) DCs in regulating immunity and tolerance [7], (ii) B cells in the C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 46-57 Cellular immune response 47 adaptive immune response, and (iii) regulatory T (Treg) cells in maintaining T-cell tolerance, we evaluated the importance of DC, B-cell, and Treg-cell activation and generation by ligandbound TLR7 in the framework of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). MS is an immune-mediated disease of the central nervous system (CNS), characterized by the infiltration of inflammatory cells, including autoreactive CD4 + T cells and antigen-presenting cells (APCs), which leads to demyelination and axonal damage [8]. Even though CD4 + T-cell autorea...

IgG bears asparagine-linked oligosaccharide side chains in the Fc region. Variations in their extent of galactosylation and sialylation could modulate IgG Fc-dependent effector functions, and hence Ab activity. However, it has not yet been clarified whether the pathogenic potential of IgG autoantibodies is consistently enhanced by the absence of galactose residues per se or the lack of terminal sialylation, which is dependent on galactosylation. Moreover, it remains to be defined whether the increased pathogenicity of agalactosylated IgG is related to activation of the complement pathway by mannose-binding lectin, as suggested by in vitro studies. Using a murine model of autoimmune hemolytic anemia, we defined the contribution of galactosylation or sialylation to the pathogenic activity of IgG1 and IgG2a anti-erythrocyte class-switch variants of 34-3C monoclonal autoantibody. We generated their degalactosylated or highly sialylated glycovariants and compared their pathogenic effects with those of highly galactosylated or desialylated counterparts. Our results demonstrated that lack of galactosylation, but not sialylation, enhanced the pathogenic activity of 34-3C IgG1, but not IgG2a autoantibodies. Moreover, analysis of in vivo complement activation and of the pathogenic activity in mice deficient in C3 or IgG FcRs excluded the implication of mannose-binding lectin-mediated complement activation in the enhanced pathogenic effect of agalactosylated IgG1 anti-erythrocyte autoantibodies.

Autoantibodies contribute to the development of systemic lupus erythematosus (SLE). APRIL (a proliferation-inducing ligand), a member of the TNF superfamily, regulates plasma-cell survival and binds to TACI (transmembrane activator CAML interactor) and BCMA (B-cell maturation antigen). We previously showed that APRIL blockade delayed disease onset in lupus-prone mice. In order to evaluate the role of APRIL receptors in the development of SLE, APRIL, TACI, BCMA, or double TACI.BCMA null mutations were introduced into the Nba2.Yaa (Y-linked autoimmune acceleration) spontaneous lupus mouse model. Mortality as a consequence of glomerulonephritis (GN) was reduced in Nba2.APRIL .Yaa, Nba2.TACI .Yaa and double-KO mice compared with Nba2.Yaa mice and correlated with lower levels of circulating antibodies, while splenic populations remained unchanged. In contrast, the appearance of symptoms was accelerated in BCMA-deficient mice, in which TACI signaling was increased. Finally, lupus-prone mice deficient for the APRIL-TACI axis produced less pathogenic antibodies and developed less GN. Disease reduction was attributed to impaired T-independent type 2 responses when the APRIL-TACI signaling axis was disrupted. Collectively, our results have identified and confirmed APRIL as a new target involved in B-cell activation, in the maintenance of plasma cell survival and subsequent increased autoantibody production that sustains lupus development in mice.