5-HT modulation of pain perception in humans

© 2017, The Author(s). Introduction: Although there is clear evidence for the serotonergic regulation of descending control of pain in animals, little direct evidence exists in humans. The majority of our knowledge comes from the use of serotonin (5-HT)-modulating antidepressants as analgesics in the clinical management of chronic pain. Objectives: Here, we have used an acute tryptophan depletion (ATD) to manipulate 5-HT function and examine its effects of ATD on heat pain threshold and tolerance, attentional manipulation of nociceptive processing and mood in human volunteers. Methods: Fifteen healthy participants received both ATD and balanced amino acid (BAL) drinks on two separate sessions in a double-blind cross-over design. Pain threshold and tolerance were determined 4 h post-drink via a heat thermode. Additional attention, distraction and temperature discrimination paradigms were completed using a laser-induced heat pain stimulus. Mood was assessed prior and throughout each session. Results: Our investigation reported that the ATD lowered plasma TRP levels by 65.05 ± 7.29% and significantly reduced pain threshold and tolerance in response to the heat thermode. There was a direct correlation between the reduction in total plasma TRP levels and reduction in thermode temperature. In contrast, ATD showed no effect on laser-induced pain nor significant impact of the distraction-induced analgesia on pain perception but did reduce performance of the painful temperature discrimination task. Importantly, all findings were independent of any effects of ATD on mood. Conclusion: As far as we are aware, it is the first demonstration of 5-HT effects on pain perception which are not confounded by mood changes

Role of macrophages from LDV-infected mice in the onset of blood autoimmune diseases

Environmental factors such as invading pathogens modify the microenvironment of the host. Since the microenvironment is responsible for the differenciation of immune cells and their subsequent effectors functions, modification of this microenvironment is responsible for a modulation of immune responses. Further, viral infections have been associated with the development of autoimmunity through several mechanisms including immunomodulation. During LDV infection, many cytokines are produced including both type I and type II IFNs which are known to be involved in macrophage differenciation. IFN-γ activates the phagocytic activity of macrophages, and therefore enhances the pathogenicity of self-reacting antibodies leading to an exacerbation of blood autoimmune diseases, while type I IFNs play a protective role by reducing phagocytosis of these immune complexes. We found that activating FcγRs are necessary to the development of severe anemia in infected mice treated with IgG2a anti-red blood cell antibodies. We analysed the mechanisms triggered by both type I and type II IFNs on the expression of FcγRs and showed an opposite regulation for FcγR I and FcγR IV by these cytokines that could not fully explain the protective role of type I IFNs in vivo. LDV infection also exacerbates the pathogenicity of IgM anti-platelet antibodies leading to the development of autoimmune thrombocytopenia (AITP). To date no receptor mediating uptake of IgM-opsonized particules could be incriminated in the disease. We therefore investigated the involvement of the recently discovered FcαμR, the only IgM receptor expressed by macrophages and showed a role of this receptor in IgM-mediated thrombocytopenia. Finally, we showed that the modifications of the microenvironment triggered by LDV lead to the differenciation of macrophages into an atypical M1 since they express many markers of M1 but also a few markers of M2 macrophages. They have reduced ability to induce T cell proliferation and decreased redifferenciation abilities although they exhibit enhanced phagocytosis leading to the exacerbation of both AIHA and AITP.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 201

Antibody-independent thrombocytopenia in lactate dehydrogenase-elevating virus-infected mice.

Previously we demonstrated that antibody-mediated thrombocytopenia is strongly enhanced by lactate dehydrogenase-elevating virus (LDV) infection. Here we report that mice infected with LDV develop a moderate thrombocytopenia, even in the absence of immunoglobulins or Fc receptors. A similar decrease of platelet counts was observed after mouse hepatitis virus infection. LDV-induced type I interferon-independent thrombocytopenia was partly suppressed by treatment with clodronate-containing liposomes. Therefore, we conclude that the thrombocytopenia results from increased phagocytosis of nonopsonized platelets by macrophages

Involvement of Fcα/μ Receptor in IgM Anti-Platelet, but Not Anti-Red Blood Cell Autoantibody Pathogenicity in Mice.

IgM anti-mouse platelet autoantibodies cause thrombocytopenia by mediating uptake of opsonized thrombocytes, whereas IgM anti-erythrocyte autoantibodies induce anemia through a phagocytosis-independent cell destruction. In this article, we show that infection with lactate dehydrogenase-elevating virus, a benign mouse arterivirus, exacerbates the pathogenicity of IgM anti-platelet, but not anti-erythrocyte autoantibodies. To define the role of Fcα/μ receptor (Fcα/μR) in IgM-mediated thrombocytopenia and anemia, we generated mice deficient for this receptor. These animals were resistant to IgM autoantibody-mediated thrombocytopenia, but not anemia. However, the lactate dehydrogenase-elevating virus-induced exacerbation of thrombocytopenia was not associated with enhanced Fcα/μR expression on macrophages. These results indicate that Fcα/μR is required for the pathogenicity of IgM anti-platelet autoantibodies but is not sufficient to explain the full extent of the disease in virally infected animals

Involvement of Virus-Induced Interferon Production in IgG Autoantibody-Mediated Anemia

Infection with viruses, such as the lactate dehydrogenase-elevating virus (LDV), is known to trigger the onset of autoimmune anemia through the enhancement of the phagocytosis of autoantibody-opsonized erythrocytes by activated macrophages. Type I interferon receptor-deficient mice show enhanced anemia, which suggests a protective effect of these cytokines, partly through the control of type II interferon production. The development of anemia requires the expression of Fcγ receptors (FcγR) I, III, and IV. Whereas LDV infection decreases FcγR III expression, it enhances FcγR I and IV expression in wild-type animals. The LDV-associated increase in the expression of FcγR I and IV is largely reduced in type I interferon receptor-deficient mice, through both type II interferon-dependent and -independent mechanisms. Thus, the regulation of the expression of FcγR I and IV, but not III, by interferons may partly explain the exacerbating effect of LDV infection on anemia that results from the enhanced phagocytosis of IgG autoantibody-opsonized erythrocytes