M2 macrophages suppress inflammation in numerous disorders, including tumour formation, infection and obesity. However, the exact role of M2 macrophages in the context of several other diseases is still largely undefined. We here show that human M2 macrophages promote inflammation instead of suppressing inflammation on simultaneous exposure to complexed IgG (c-IgG) and TLR ligands, as occurs in the context of diseases such as rheumatoid arthritis (RA). c-IgG-TLR ligand co-stimulation of M2 macrophages selectively amplifies production of pro-inflammatory cytokines TNF-α, IL-1β and IL-6 and promotes Th17 responses, which all play a critical role in RA pathology. Induction of pro-inflammatory cytokines on c-IgG co-stimulation mainly depends on Fc gamma receptor IIa (FcγRIIa), which selectively amplifies cytokine gene transcription and induces caspase-1 activation. These data indicate that FcγR-TLR cross-talk may be targeted for treatment to attenuate inflammation in RA, by restoring the anti-inflammatory function of M2 macrophages.

The prevailing concept regarding the immunological function of immunoglobulin A (IgA) is that it binds to and neutralizes pathogens to prevent infection at mucosal sites of the body. However, recently, it has become clear that in humans IgA is also able to actively contribute to the initiation of inflammation, both at mucosal and non-mucosal sites. This additional function of IgA is initiated by the formation of immune complexes, which trigger Fc alpha Receptor I (FcαRI) to synergize with various other receptors to amplify inflammatory responses. Recent findings have demonstrated that co-stimulation of FcαRI strongly affects pro-inflammatory cytokine production by various myeloid cells, including different dendritic cell subsets, macrophages, monocytes, and Kupffer cells. FcαRI-induced inflammation plays a crucial role in orchestrating human host defense against pathogens, as well as the generation of tissue-specific immunity. In addition, FcαRI-induced inflammation is suggested to be involved in the pathogenesis of various chronic inflammatory disorders, including inflammatory bowel disease, celiac disease, and rheumatoid arthritis. Combined, IgA-induced inflammation may be used to either promote inflammatory responses, e.g. in the context of cancer therapy, but may also provide new therapeutic targets to counteract chronic inflammation in the context of various chronic inflammatory disorders.

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IgA is predominantly recognized to play an important role in host defense at mucosal sites, where it prevents invasion of pathogens by neutralization. Although it has recently become clear that IgA also mediates other immunological processes, little remains known about the potential of IgA to actively contribute to induction of inflammation, particularly in nonmucosal organs and tissues. In this article, we provide evidence that immune complex formation of serum IgA plays an important role in orchestration of inflammation in response to pathogens at various nonmucosal sites by eliciting proinflammatory cytokines by human macrophages, monocytes, and Kupffer cells. We show that opsonization of bacteria with serum IgA induced cross-talk between FcαRI and different TLRs, leading to cell type-specific amplification of proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IL-23. Furthermore, we demonstrate that the increased protein production of cytokines was regulated at the level of gene transcription, which was dependent on activation of kinases Syk and PI3K. Taken together, these data demonstrate that the immunological function of IgA is substantially more extensive than previously considered and suggest that serum IgA-induced inflammation plays an important role in orchestrating host defense by different cell types in nonmucosal tissues, including the liver, skin, and peripheral blood.

CD103+ dendritic cells (DC) are crucial for regulation of intestinal tolerance in humans. However, upon infection of the lamina propria this tolerogenic response is converted to an inflammatory response. Here we show that immunoglobulin A (IgA) immune complexes (IgA-IC), which are present after bacterial infection of the lamina propria, are important for the induction of inflammation by the human CD103+SIRPα+ DC subset. IgA-IC, by recognition through FcαRI, selectively amplify the production of proinflammatory cytokines TNF, IL-1β and IL-23 by human CD103+ DCs. These cells then enhance inflammation by promoting Th17 responses and activating human intestinal innate lymphoid cells 3. Moreover, FcαRI-induced cytokine production is orchestrated via upregulation of cytokine translation and caspase-1 activation, which is dependent on glycolytic reprogramming mediated by kinases Syk, PI3K and TBK1-IKKε. Our data suggest that the formation of IgA-IC in the human intestine provides an environmental cue for the conversion of a tolerogenic to an inflammatory response.

Antigen-presenting cells (APCs) such as dendritic cells (DCs) are crucial for initiation of adequate inflammatory responses, which critically depends on the cooperated engagement of different receptors. In addition to pattern recognition receptors (PRRs), Fc gamma receptors (FcγRs) have recently been identified to be important in induction of inflammation by DCs. FcγRs that recognize IgG immune complexes, which are formed upon opsonization of pathogens, induce pro-inflammatory cytokine production through cross-talk with PRRs such as Toll-like receptors (TLRs). While the physiological function of FcγR-TLR cross-talk is to provide protective immunity against invading pathogens, undesired activation of FcγR-TLR cross-talk, e.g., by autoantibodies, also plays a major role in the development of chronic inflammatory disorders such as rheumatoid arthritis (RA). Yet, the molecular mechanisms of FcγR-TLR cross-talk are still largely unknown. Here, we identified that FcγR-TLR cross-talk-induced cytokine production critically depends on activation of the transcription factor interferon regulatory factor 5 (IRF5), which results from induction of two different pathways that converge on IRF5 activation. First, TLR stimulation induced phosphorylation of TBK1/IKKε, which is required for IRF5 phosphorylation and subsequent activation. Second, FcγR stimulation induced nuclear translocation of IRF5, which is essential for gene transcription by IRF5. We identified that IRF5 activation by FcγR-TLR cross-talk amplifies pro-inflammatory cytokine production by increasing cytokine gene transcription, but also by synergistically inducing glycolytic reprogramming, which is another essential process for induction of inflammatory responses by DCs. Combined, here we identified IRF5 as a pivotal component of FcγR-TLR cross-talk in human APCs. These data may provide new potential targets to suppress chronic inflammation in autoantibody-associated diseases that are characterized by undesired or excessive FcγR-TLR cross-talk, such as RA, systemic sclerosis, and systemic lupus erythematous.

SummaryNeutrophil recruitment is essential in clearing pneumococcal infections. The first step in neutrophil extravasation involves the interaction between P-selectin on activated endothelium and P-Selectin Glycoprotein 1 (PSGL-1) on neutrophils. Here, we identify pneumococcal Zinc metalloproteinase C as a potent inhibitor of PSGL-1. ZmpC degrades the N-terminal domain of PSGL-1, thereby disrupting the initial rolling of neutrophils on activated human umbilical vein endothelial cells. Furthermore, mice infected with wild-type strain in the model of pneumococcal pneumonia showed lower lungs neutrophil infiltration compare to animals infected with ZmpC mutant. In addition, we confirmed the association of zmpC with serotype 8 and 11A and found it to be associated with serotype 33F as well. In conclusion, we report PSGL-1 as a novel target for ZmpC and show that ZmpC inhibits neutrophil extravasation during pneumococcal pneumonia.

Objective and design To determine whether ER stress affects the inhibitory pathways of the human immune system, particularly the immunosuppressive effect of IL-10 on macrophages. Material or subjects In vitro stimulation of human monocyte-derived macrophages. Treatment Cells were stimulated with TLR ligands and IL-10, while ER stress was induced using thapsigargin or tunicamycin. Methods mRNA expression was determined using qPCR, while cytokine protein production was measured using ELISA. Protein expression of receptors and transcription factors was determined using flow cytometry. Student’s t test was used for statistics. Results While under normal conditions IL-10 potently suppresses pro-inflammatory cytokine production by LPS-stimulated macrophages, we demonstrate that ER stress counteracts the immunosuppressive effects of IL-10, leading to increased pro-inflammatory cytokine production. We identified that ER stress directly interferes with IL-10R signaling by reducing STAT3 phosphorylation on Tyr705, which thereby inhibits the expression of SOCS3. Moreover, we show that ER stress also inhibits STAT3 activation induced by other receptors such as IL-6R. Conclusions Combined, these data uncover a new general mechanism by which ER stress promotes inflammation. Considering its potential involvement in the pathogenesis of diseases such as Crohn’s disease and spondyloarthritis, targeting of this mechanism may provide new opportunities to counteract inflammation.