Free-energy pragmatics: Markov blankets don't prescribe objective ontology, and that's okay.

We target the ontological and epistemological ramifications of the proposed distinction between Friston and Pearl blankets. We emphasize the need for empirical testing next to computational modeling. A peculiar aspect of the free energy principle (FEP) is its purported support of radically opposed ontologies of the mind. In our view, the objective ontological aspiration itself should be rejected for a pragmatic instrumentalist view.

Enactive-Dynamic Social Cognition and Active Inference.

This aim of this paper is two-fold: it critically analyses and rejects accounts blending active inference as theory of mind and enactivism; and it advances an enactivist-dynamic understanding of social cognition that is compatible with active inference. While some social cognition theories seemingly take an enactive perspective on social cognition, they explain it as the attribution of mental states to other people, by assuming representational structures, in line with the classic Theory of Mind (ToM). Holding both enactivism and ToM, we argue, entails contradiction and confusion due to two ToM assumptions widely known to be rejected by enactivism: that (1) social cognition reduces to mental representation and (2) social cognition is a hardwired contentful 'toolkit' or 'starter pack' that fuels the model-like theorising supposed in (1). The paper offers a positive alternative, one that avoids contradictions or confusion. After rejecting ToM-inspired theories of social cognition and clarifying the profile of social cognition under enactivism, that is without assumptions (1) and (2), the last section advances an enactivist-dynamic model of cognition as dynamic, real-time, fluid, contextual social action, where we use the formalisms of dynamical systems theory to explain the origins of socio-cognitive novelty in developmental change and active inference as a tool to demonstrate social understanding as generalised synchronisation.

Intradermal delivery of TLR agonists in a human explant skin model: preferential activation of migratory dendritic cells by polyribosinic-polyribocytidylic acid and peptidoglycans.

TLR agonists are attractive candidate adjuvants for therapeutic cancer vaccines as they can induce a balanced humoral and T cell-mediated immune response. With a dense network of dendritic cells (DCs) and draining lymphatics, the skin provides an ideal portal for vaccine delivery. Beside direct DC activation, TLR agonists may also induce DC activation through triggering the release of inflammatory mediators by accessory cells in the skin microenvironment. Therefore, a human skin explant model was used to explore the in vivo potential of intradermally delivered TLR agonists to stimulate Langerhans cells and dermal DCs in their natural complex tissue environment. The skin-emigrated DCs were phenotyped and analyzed for T cell stimulatory capacity. We report that, of six tested TLR-agonists, the TLR2 and -3 agonists peptidoglycan (PGN) and polyribosinic-polyribocytidylic acid (Poly I:C) were uniquely able to enhance the T cell-priming ability of skin-emigrated DCs, which, in the case of PGN, was accompanied by Th1 polarization. The enhanced priming capacity of Poly I:C-stimulated DCs was associated with a strong upregulation of appropriate costimulatory molecules, including CD70, whereas that of PGN-stimulated DCs was associated with the release of a broad array of proinflammatory cytokines. Transcriptional profiling further supported the notion that the PGN- and Poly I:C-induced effects were mediated through binding to TLR2/nucleotide-binding oligomerization domain 2 and TLR3/MDA5, respectively. These data warrant further exploration of PGN and Poly I:C, alone or in combination, as DC-targeted adjuvants for intradermal cancer vaccines.

Cellular players in lung fibrosis.

Pathogenic mechanisms involved in fibrosis of various organs share many common features. Myofibroblasts are thought to play a major role in fibrosis through excessive deposition of extracellular matrix during wound healing processes. Myofibroblasts are observed in fibrotic lesions, and whereas these derive from the hepatic stellate cells in liver, in lung they appear to originate from fibroblasts. The source of these fibroblasts has been the object of numerous studies over the recent years and points towards multiple sources. First of all, resident fibroblasts are thought to differentiate into the more contractile myofibroblasts, secreting many extracellular matrix proteins. Secondly, the epithelial to mesenchymal transition (EMT) of epithelial cells may also account for increased numbers of fibroblasts, though in vivo evidence in patient tissue is still scarce. Thirdly, the enigmatic fibrocytes, stemming from the bone marrow, may also account for increasing numbers of fibroblasts in fibrotic lesions. These pathogenic processes are further augmented by the generation of so-called alternatively activated macrophages, which have direct and indirect effects on myofibroblast accumulation and collagen deposition. TGFß, which is produced predominantly by macrophages, plays a central role in all these processes by inducing EMT, driving differentiation of fibrocytes, and differentiation towards myofibroblasts. This review describes the potential origins and roles of these fibrotic cells in the lung and discusses models to study these cells in vitro. These models offer innovative approaches in target and drug discovery, aiming to uncover novel therapeutic targets that regulate the profibrotic phenotype of these cells.

A step-by-step approach to study the influence of N-acetylation on the adjuvanticity of N,N,N-trimethyl chitosan (TMC) in an intranasal nanoparticulate influenza virus vaccine.

Recently we reported that reacetylation of N,N,N-trimethyl chitosan (TMC) reduced the adjuvant effect of TMC in mice after intranasal (i.n.) administration of whole inactivated influenza virus (WIV) vaccine. The aim of the present study was to elucidate the mechanism of this lack of adjuvanticity. Reacetylated TMC (TMC-RA, degree of acetylation 54%) was compared with TMC (degree of acetylation 17%) at six potentially critical steps in the induction of an immune response after i.n. administration in mice. TMC-RA was degraded in a nasal wash to a slightly larger extent than TMC. The local i.n. distribution and nasal clearance of WIV were similar for both TMC types. Fluorescently labeled WIV was taken up more efficiently by Calu-3 cells when formulated with TMC-RA compared to TMC and both TMCs significantly reduced transport of WIV over a Calu-3 monolayer. Murine bone-marrow derived dendritic cell activation was similar for plain WIV, and WIV formulated with TMC-RA or TMC. The inferior adjuvant effect in mice of TMC-RA over that of TMC might be caused by a slightly lower stability of TMC-RA-WIV in the nasal cavity, rather than by any of the other factors studied in this paper.

IL-15 aggravates atherosclerotic lesion development in LDL receptor deficient mice.

BACKGROUND: Interleukin 15 (IL-15) is a pro-inflammatory cytokine involved in inflammatory diseases and IL-15 is expressed in atherosclerotic plaques. METHODS: To establish the role of IL-15 in atherosclerosis we studied the effect of IL-15 on atherosclerosis associated cells in vitro and in vivo by neutralizing IL-15 using a DNA vaccination strategy. RESULTS: Upon feeding a Western type diet LDLr(-/-) mice do express higher levels of IL-15 within the spleen and the number of IL-15 expressing cells among blood leukocytes and spleen cells is increased. Addition of IL-15 to macrophages induces the expression TNF-α and CCL-2. After the mice were vaccinated against IL-15, we observe a reduction in plaque size of 75% plaque. Unexpectedly, the relative number of macrophages within the plaque was 2-fold higher in IL-15 vaccinated mice than in control mice. Vaccination against IL-15 leads to an increased cytotoxicity against IL-15 overexpressing target cells, resulting in a reduction in IL-15 expressing cells and macrophages in blood and spleen and a decreased CD4/CD8 ratio. CONCLUSION: Hypercholesterolemia leads to upregulation of IL-15 within spleen and blood. DNA vaccination against IL-15 does markedly reduces atherosclerotic lesion size, but does not promote lesion stability.

A vaccine against atherosclerosis: myth or reality?

Atherosclerosis is a chronic inflammatory disease that develops in the context of enhanced serum lipid levels. Nowadays, many studies focus on the modulation of inflammatory responses to reduce atherosclerosis. The most powerful strategy to achieve this is vaccination. In several immune diseases vaccination is shown to be very effective, resulting in a drastic decline in the incidence of the disease. But is vaccination also realistic in atherosclerosis? In this article, several approaches to vaccinate against atherosclerosis are described. Vaccination (based on protein or DNA) against bioactive molecules and disease-related proteins successfully reduces experimental atherosclerosis. In addition, passive immunization with antibodies against atherosclerosis-specific antigens and tolerance induction, in which antigen-specific regulatory T cells are elicited, are described. In the near future, we expect an increased interest in vaccination against atherosclerosis and, maybe, the myth may become reality when the first clinical trials are performed.

CXCR3 antagonist NBI-74330 attenuates atherosclerotic plaque formation in LDL receptor-deficient mice.

OBJECTIVE: The chemokine receptor CXCR3 is implicated in migration of leukocytes to sites of inflammation. Antagonizing CXCR3 may be a strategy to inhibit inflammation-induced leukocyte migration and subsequently reduce atherosclerosis. We used the CXCR3 specific antagonist NBI-74330 to block CXCR3-mediated signaling in peritonitis and diet-induced atherosclerosis. METHODS AND RESULTS: Antagonizing CXCR3 with NBI-74330 resulted in a significant reduction in CD4+ T cell and macrophage migration to the peritoneal cavity, which was as shown in ex vivo migration studies totally CXCR3 dependent. Atherosclerotic lesion formation in the aortic valve leaflet area and the entire aorta was significantly inhibited in NBI-74330 treated mice. Lymph nodes draining from the aortic arch were significantly smaller in treated mice and were enriched in regulatory T cells and contained fewer activated T cells, whereas the markers for regulatory T cells within the lesion were enhanced after NBI-74330 treatment. CONCLUSIONS: This study shows for the first time that treatment with a CXCR3 antagonist results in attenuating atherosclerotic lesion formation by blocking direct migration of CXCR3+ effector cells from the circulation into the atherosclerotic plaque and by beneficially modulating the inflammatory response in the lesion and the lymph nodes draining from the atherosclerotic lesion.

Immunomodulation of the inflammatory response in atherosclerosis.

PURPOSE OF REVIEW: Cardiovascular disease, as manifested in the formation of atherosclerotic lesions, can be described as a chronic inflammatory autoimmune-like disease that proceeds in the context of enhanced plasma lipid levels. Modulation of the immune response may therefore form a valuable therapy in addition to standardized cholesterol and blood pressure-lowering therapies. The purpose of this review is to describe a number of recent approaches to immunomodulate atherosclerosis: immunization against mediators involved in atherosclerosis, such as cytokines and modified low-density lipoprotein; intervention in cytokine pathways; intervention in co-stimulatory pathways; activation of regulatory T cells; and modulation of natural killer T cells. RECENT FINDINGS: The most recent findings point to an important role for regulatory T cells in atherosclerotic lesion formation. The function of the regulatory T cells is modulated by chemokines and by co-stimulatory pathways, whereas the function of these cells can be strongly upregulated by anti-CD3 treatment and tolerance induction. SUMMARY: In the near future the first exponents of this approach, such as immunization and enhancement of the function of regulatory T cells, may enter the first phase of clinical trials, and may ultimately add to the current therapies in atherosclerosis.