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The hormone and neurotransmitter serotonin regulates numerous physiological functions within the central nervous system and in the periphery upon binding to specific receptors. In the periphery, the serotonin receptor 7 (5-HT7R) is expressed on different immune cells including monocytes and macrophages. To investigate the impact of 5-HT7R-mediated signaling on macrophage properties, we used human THP-1 cells and differentiated them into pro-inflammatory M1- and anti-inflammatory M2-like macrophages. Pharmacological 5-HT7R activation with the specific agonist LP-211 especially modulates morphology of M1-like macrophages by increasing the number of rounded cells. Furthermore, 5-HT7R stimulation results in significantly reduced phagocytic and migratory ability of M1-like macrophages. Noteworthy, LP-211 treatment leads to changes in secretory properties of all macrophage types with the highest effects obtained for M0- and M2c-like macrophages. Finally, the importance of 5-HT7R for regulation of phagocytosis was confirmed in human primary CD14 + cells. These results indicate that 5-HT7R activation selectively impairs basic functions of macrophages and might thus be a new access point for the modulation of macrophage responses in the future treatment of inflammatory diseases., Competing Interests: Declarations. Ethical approval: Not applicable. Consent for publication: The authors hereby consent to publication of the work in Cellular and Molecular Life Sciences. Competing interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2025. The Author(s).)

Older organs represent an untapped potential to close the gap between demand and supply in organ transplantation but are associated with age-specific responses to injury and increased immunogenicity, thereby aggravating transplant outcomes. Here we show that cell-free mitochondrial DNA (cf-mt-DNA) released by senescent cells accumulates with aging and augments immunogenicity. Ischemia reperfusion injury induces a systemic increase of cf-mt-DNA that promotes dendritic cell-mediated, age-specific inflammatory responses. Comparable events are observed clinically, with the levels of cf-mt-DNA elevated in older deceased organ donors, and with the isolated cf-mt-DNA capable of activating human dendritic cells. In experimental models, treatment of old donor animals with senolytics clear senescent cells and diminish cf-mt-DNA release, thereby dampening age-specific immune responses and prolonging the survival of old cardiac allografts comparable to young donor organs. Collectively, we identify accumulating cf-mt-DNA as a key factor in inflamm-aging and present senolytics as a potential approach to improve transplant outcomes and availability.

Schizophrenia and major depression are associated with alterations in peripheral inflammatory markers, and anti-inflammatory therapy has been proposed as a promising add-on approach in the pharmacologic treatment of both disorders. Second-generation atypical antipsychotics are currently first-line drugs in the treatment of schizophrenia and are also used as augmentation strategies in treatment-resistant major depression. Furthermore, these drugs have been reported to exhibit distinct metabolic side effects and to influence inflammatory processes. In this study, we used ex vivo stimulation of primary human peripheral blood mononuclear cells (PBMC) from healthy blood donors with atypical antipsychotics olanzapine or aripiprazole to examine effects on cytokine production independent from metabolic side effects and disease status. Both olanzapine and aripiprazole stimulation decreased mRNA levels of IL-1β, IL-6, and TNF-α and resulted in diminished protein concentrations of IL-6 and TNF-α in conditioned medium of stimulated PBMC. A multiplex approach revealed additional downregulation of IL-2; MIP-1β and IP-10 secretion. Similarly, olanzapine and aripiprazole stimulation of the human monocytic cell line THP-1 resulted in a significant decrease in expression and secretion of IL-1β and TNF-α. Our results suggest that atypical antipsychotics directly influence immune cell function and thereby highlight the importance to factor in potential side effects of drugs routinely used in treatment of schizophrenia and major depression on inflammatory processes when considering anti-inflammatory drug therapy as an additional treatment option., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Inflammation plays an important role in atherosclerosis, a notion supported by the beneficial effects of the IL-1β inhibitor canakinumab in the CANTOS trial. Sialic acids (Sias), components of the surface glycocalyx, regulate intercellular and intermolecular interactions. We investigated the expression of the Sia cleaving enzyme neuraminidase-1 (NEU1) in atherosclerotic plaques and its potential role in inflammatory processes. In isolated mononuclear blood cells from patients with myocardial infarction, NEU1 expression was increased compared to healthy controls. High expression of NEU1 in macrophages located on the intima layer, in calcified regions and the adventitia of the plaque was observed in human carotid arteries' atherectomies. IL-1β and LPS induced NEU1 expression in THP-1 monocytic cells. Lentiviral NEU1-overexpression in THP-1-cells enhanced expression of CD80, TNF-α, IL-1β, number of multinuclear cells, phagocytosis and chemotaxis indicative for M1 monocyte/macrophage polarization. CRISPR/Cas9-mediated knock-out of NEU1 in THP-1-cells did not affect differentiation of monocytes to macrophages but attenuated LPS- and IL-1β -induced TNF-α and IL-1β expression. SiRNA-mediated knock-down of NEU1 in M1-macrophages differentiated from primary human CD14 + monocytes reduced the expression of TNF-α and IL-1β. Thus, in monocytes/macrophages, LPS, NEU1 and IL-1β act in a positive feedback loop as enhancers of inflammation and may therefore promote atherosclerosis and plaque instability., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Crohn's disease (CD) is a chronic inflammatory disorder of the human gastrointestinal tract. Although genetic, immunological, environmental, and bacterial factors have been implicated, the pathogenesis is incompletely understood. The histopathological appearance of CD strikingly resembles Johne's disease, a ruminant inflammatory bowel disease, caused by Mycobacterium avium ssp. paratuberculosis (MAP), but a causative role of MAP in CD has not been established. In this work, we hypothesized that MAP might exacerbate an already existing intestinal disease., Methods: We combined dextran sulfate sodium (DSS)-induced colitis with MAP infection in mice and monitored the immune response and bacterial count in different organs., Results: An increased size of liver and spleen was observed in DSS-treated and MAP-infected animals (DSS + MAP) as compared with DSS-treated uninfected (DSS + PBS) mice. Similarly, DSS treatment increased the number and size of MAP-induced liver granulomas and enhanced the MAP counts in enteric tissue. MAP infection in turn delayed the mucosal healing of DSS-induced tissue damage. Finally, high numbers of MAP were found in mesenteric fat tissue causing large granuloma and necrotic regions., Conclusions: Taken together, we present an in vivo model to study the role of MAP infection in CD. Our results confirm the hypothesis that MAP is able to exacerbate existing intestinal inflammation.

Tumor microenvironment is characterized by chronic inflammation represented by infiltrating leukocytes and soluble mediators, which lead to a local and systemic immunosuppression associated with cancer progression. Here, we used the ret transgenic spontaneous murine melanoma model that mimics human melanoma. Skin tumors and metastatic lymph nodes showed increased levels of inflammatory factors such as IL-1β, GM-CSF, and IFN-γ, which correlated with tumor progression. Moreover, Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs), known to inhibit tumor reactive T cells, were enriched in melanoma lesions and lymphatic organs during tumor progression. MDSC infiltration was associated with a strong TCR ζ-chain down-regulation in all T cells. Coculturing normal splenocytes with tumor-derived MDSC induced a decreased T-cell proliferation and ζ-chain expression, verifying the MDSC immunosuppressive function and suggesting that the tumor inflammatory microenvironment supports MDSC recruitment and immunosuppressive activity. Indeed, upon manipulation of the melanoma microenvironment with the phosphodiesterase-5 inhibitor sildenafil, we observed reduced levels of numerous inflammatory mediators (e.g., IL-1β, IL-6, VEGF, S100A9) in association with decreased MDSC amounts and immunosuppressive function, indicating an antiinflammatory effect of sildenafil. This led to a partial restoration of ζ-chain expression in T cells and to a significantly increased survival of tumor-bearing mice. CD8 T-cell depletion resulted in an abrogation of sildenafil beneficial outcome, suggesting the involvement of MDSC and CD8 T cells in the observed therapeutic effects. Our data imply that inhibition of chronic inflammation in the tumor microenvironment should be applied in conjunction with melanoma immunotherapies to increase their efficacy.

Summary: Background and Aims: Non‐selective beta‐blockers (NSBB) are a well‐established treatment in patients with clinically significant portal hypertension. However, their potential role after insertion of a transjugular intrahepatic portosystemic shunt (TIPS) still needs to be determined. Of note, recent studies suggested that favourable anti‐inflammatory effects of NSBB might be independent from pressure reduction. This study aimed to evaluate whether NSBB‐treatment is associated with amelioration of systemic inflammation (SI), hepatic decompensation and survival after TIPS‐insertion. Methods: In a retrospective study comprising 305 consecutive patients, we investigated the impact of NSBB‐intake at TIPS‐placement on periinterventional cirrhosis‐associated complications and continued NSBB‐treatment after discharge on complications including hepatic decompensation and mortality during 1‐year follow‐up, employing multivariable competing‐risk‐analyses. In a prospective cohort including 45 patients, we performed a comprehensive analysis of SI analysing 48 soluble inflammatory markers (SIMs) at baseline plus 3 and 6 months after TIPS‐insertion. Results: Overall, 175 (57.4%) patients received NSBB‐therapy prior to TIPS‐insertion; upon discharge, this decreased to 131 (22.9%), with 36 (27.5%) discontinuing NSBB within 1‐year follow‐up. Neither NSBB‐therapy at TIPS‐insertion nor treatment‐continuation after discharge were associated with lower risks for hepatic decompensation, individual cirrhosis‐associated complications or mortality neither in the periinterventional period nor during follow‐up. Similarly, in the prospective cohort NSBB‐intake was not linked to lower levels or a more prominent change of WBC, CRP or any other SIM at any of the investigated time points. Conclusion: NSBB‐therapy at the time of TIPS‐insertion and its (dis‐)continuation afterwards seems to have no significant impact on SI, development of hepatic decompensation and survival. [ABSTRACT FROM AUTHOR]

During influenza A virus (IAV) infections, CD4+ T cell responses within infected lungs mainly involve T helper 1 (Th1) and regulatory T cells (Tregs). Th1-mediated responses favor the co-expression of T-box transcription factor 21 (T-bet) in Foxp3+ Tregs, enabling the efficient Treg control of Th1 responses in infected tissues. So far, the exact accumulation kinetics of T cell subsets in the lungs and lung-draining lymph nodes (dLN) of IAV-infected mice is incompletely understood, and the epigenetic signature of Tregs accumulating in infected lungs has not been investigated. Here, we report that the total T cell and the two-step Treg accumulation in IAV-infected lungs is transient, whereas the change in the ratio of CD4+ to CD8+ T cells is more durable. Within lungs, the frequency of Tregs co-expressing T-bet is steadily, yet transiently, increasing with a peak at Day 7 post-infection. Interestingly, T-bet+ Tregs accumulating in IAV-infected lungs displayed a strongly demethylated Tbx21 locus, similarly as in T-bet+ conventional T cells, and a fully demethylated Treg-specific demethylated region (TSDR) within the Foxp3 locus. In summary, our data suggest that T-bet+ but not T-bet− Tregs are epigenetically stabilized during IAV-induced infection in the lung. [ABSTRACT FROM AUTHOR]

Abstract: CD40Ligand (CD40L) represents a strong endogenous danger signal associated with chronic inflammatory disease. CD40L induces activation of antigen-presenting cells (APCs) such as DCs, monocytes, B-cells and endothelial cells. However, CD40 activation alone, whilst inducing IL-10 production, is insufficient to induce interleukin (IL)-12p70 release in human APCs suggesting that additional cytokine signals (e.g. GM-CSF, IL-4 or IFN-γ) are required for the induction of a pro-inflammatory cytokine profile. We demonstrate that IFN-γ-induced Janus kinase 1 (JAK1) enhances CD40-induced IL-12p70 release whilst simultaneously inhibiting IL-10 synthesis, resulting in a pro-inflammatory phenotype of CD40L-activated dendritic cells (DCs). JAK2 mediated enhancing effects on IL-12p70 but did not inhibit IL-10 release, whereas Tyk2 mediated inhibitory effects on IL-12p70 release in this system. The mechanism by which complementary IFN-γ/JAK activities affect IL-12p70 production involves STAT1 activation and de novo induction of interferon-responsive factors (IRF)-1 and IRF-8. Simultaneously, JAK1 was unique in inhibiting IL-10 synthesis via STAT1 and IRF-8 with both transcription factors binding to the IL-10 promoter. We demonstrate that CD40- and JAK/STAT/IRF-signalling pathways are strictly complementary for the induction of a pro-inflammatory cytokine profile in human APCs. This suggests that a number of CD40 effects in chronic inflammatory diseases might be weakened by targeting JAK/STAT. [ABSTRACT FROM AUTHOR]