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One central mechanism, by which vitamin D regulates human immune responses, is the direct modulation of dendritic cells (DCs). However, the effect of vitamin D on several key DC functions, such as the secretion of central inflammatory cytokines, remains controversial. Moreover, whether vitamin D treatment of DCs regulates their ability to promote differentiation of IL-17-/IL-22-producing T cell subsets, such as Th17 and Th22 cell, is not known. Here, we report that vitamin D treatment during differentiation of monocytes into DCs markedly enhanced their ability to secrete TNF-α, IL-6, IL-1β and IL-23. Cytokines secreted by vitamin D-treated DC were significantly more potent in driving differentiation of IL-22-producing T cells, but not IL-17-producing T cells, as compared to secreted cytokines of not-vitamin D-treated DCs. Finally, we found that the differentiation of IL-22-producing T cells mediated by supernatants of vitamin D-treated DCs was dependent on TNF-α IL-6 and IL-23. In summary, our study suggests a novel role of vitamin D in regulating DC-mediated immune responses in humans.

The extracellular matrix (ECM) provides structural support for tissue architecture and is a major effector of cell behavior during skin repair and inflammation. Macrophages are involved in all stages of skin repair but only limited knowledge exists about macrophage-specific expression and regulation of ECM components. In this study, we used transcriptome profiling and bioinformatic analysis to define the unique expression of ECM-associated genes in cultured macrophages. Characterization of the matrisome revealed that most genes were constitutively expressed and that several genes were uniquely regulated upon interferon gamma (IFNγ) and dexamethasone stimulation. Among those core matrisome and matrisome-associated components transforming growth factor beta (TGFβ)-induced, matrix metalloproteinase 9 (MMP9), elastin microfibril interfacer (EMILIN)-1, netrin-1 and gliomedin were also present within the wound bed at time points that are characterized by profound macrophage infiltration. Hence, macrophages are a source of ECM components in vitro as well as during skin wound healing, and identification of these matrisome components is a first step to understand the role and therapeutic value of ECM components in macrophages and during wound healing.

We investigated the mechanisms by which T-cell cytokines are able to influence the Toll-like receptor (TLR)-induced, vitamin D-dependent antimicrobial pathway in human monocytes. T-cell cytokines differentially influenced TLR2/1-induced expression of the antimicrobial peptides cathelicidin and DEFB4, being up-regulated by IFN-γ, down-regulated by IL-4, and unaffected by IL-17. The Th1 cytokine IFN-γ up-regulated TLR2/1 induction of 25-hydroxyvitamin D-1α-hydroxylase (i.e., CYP27B1), leading to enhanced bioconversion of 25-hydroxyvitamin D₃ (25D₃) to its active metabolite 1,25D₃. In contrast, the Th2 cytokine IL-4, by itself and in combination with the TLR2/1 ligand, induced catabolism of 25D₃ to the inactive metabolite 24,25D₃, and was dependent on expression of vitamin D-24-hydroxylase (i.e., CYP24A1). Therefore, the ability of T-cell cytokines to differentially control monocyte vitamin D metabolism represents a mechanism by which cell-mediated immune responses can regulate innate immune mechanisms to defend against microbial pathogens.

Leprosy is a chronic infectious disease that may present different clinical forms according to the immune response of the host. Levels of IFN-γ are significantly raised in paucibacillary tuberculoid (T-lep) when compared with multibacillary lepromatous (L-lep) patients. IFN-γ primes macrophages for inflammatory activation and induces the autophagy antimicrobial mechanism. The involvement of autophagy in the immune response against Mycobacterium leprae remains unexplored. Here, we demonstrated by different autophagic assays that LC3-positive autophagosomes were predominantly observed in T-lep when compared with L-lep lesions and skin-derived macrophages. Accumulation of the autophagic receptors SQSTM1/p62 and NBR1, expression of lysosomal antimicrobial peptides and colocalization analysis of autolysosomes revealed an impairment of the autophagic flux in L-lep cells, which was restored by IFN-γ or rapamycin treatment. Autophagy PCR array gene-expression analysis revealed a significantly upregulation of autophagy genes (BECN1, GPSM3, ATG14, APOL1, and TPR) in T-lep cells. Furthermore, an upregulation of autophagy genes (TPR, GFI1B and GNAI3) as well as LC3 levels was observed in cells of L-lep patients that developed type 1 reaction (T1R) episodes, an acute inflammatory condition associated with increased IFN-γ levels. Finally, we observed increased BCL2 expression in L-lep cells that could be responsible for the blockage of BECN1-mediated autophagy. In addition, in vitro studies demonstrated that dead, but not live M. leprae can induce autophagy in primary and lineage human monocytes, and that live mycobacteria can reduce the autophagy activation triggered by dead mycobacteria, suggesting that M. leprae may hamper the autophagic machinery as an immune escape mechanism. Together, these results indicate that autophagy is an important innate mechanism associated with the M. leprae control in skin macrophages.

The treatment of azole-resistant Trichophyton indotineae poses a significant challenge for clinicians worldwide. Resistance mechanisms include amino acid substitutions in the sterol 14-α demethylase gene Erg11B, as well as overexpression of Erg11B. Additionally, efflux mechanisms mediated by fungal transporter proteins contribute to antifungal resistance. Therefore, the inhibition of fungal efflux transporters using known inhibitors could be a promising strategy to prevent treatment failure. The inhibitory effects of itraconazole in combination with various efflux pump inhibitors were evaluated. Co-treatment with quinine hydrochloride and itraconazole did not lead to a significant reduction in the inhibitory concentration (IC) values in T. indotineae isolates. In contrast, ritonavir lowered IC values by approximately 50% without affecting fungal growth when applied as monotherapy. The most pronounced effect was observed with sertraline, which demonstrated intrinsic antifungal activity at higher concentrations. When combined with itraconazole, sertraline reduced IC values to below 10% in both susceptible and resistant strains, enhancing itraconazole efficacy markedly. The increasing prevalence of antifungal resistance is a growing global health concern. These findings suggest that sertraline holds considerable potential as an adjunctive therapy for the treatment of dermatomycoses.

In October 2016, an adolescent boy sought care for acute genital ulceration in Cologne, Germany. We presumed a sexually transmitted infection, but initial diagnostic procedures yielded negative results. He was hospitalized because swab samples from the lesion grew toxigenic Corynebacterium diphtheriae, leading to the diagnosis of possibly sexually transmitted cutaneous diphtheria.

Cutaneous granulomatoses represent a heterogeneous group of diseases, which are defined by macrophage infiltration in the skin. Skin granuloma can be formed in the context of infectious and non-infectious conditions. Recent technological advances have deepened our understanding of the pathophysiology of granulomatous skin inflammation, and they provide novel insights into human tissue macrophage biology at the site of ongoing disease. Here, we discuss findings on macrophage immune function and metabolism derived from three prototypic cutaneous granulomatoses: granuloma annulare, sarcoidosis, and leprosy.

CD4 + T cell differentiation requires metabolic reprogramming to fulfil the bioenergetic demands of proliferation and effector function, and enforce specific transcriptional programmes 1 – 3 . Mitochondrial membrane dynamics sustains mitochondrial processes 4 , including respiration and tricarboxylic acid (TCA) cycle metabolism 5 , but whether mitochondrial membrane remodelling orchestrates CD4 + T cell differentiation remains unclear. Here we show that unlike other CD4 + T cell subsets, T helper 17 (T H 17) cells have fused mitochondria with tight cristae. T cell-specific deletion of optic atrophy 1 (OPA1), which regulates inner mitochondrial membrane fusion and cristae morphology 6 , revealed that T H 17 cells require OPA1 for its control of the TCA cycle, rather than respiration. OPA1 deletion amplifies glutamine oxidation, leading to impaired NADH/NAD + balance and accumulation of TCA cycle metabolites and 2-hydroxyglutarate—a metabolite that influences the epigenetic landscape 5 , 7 . Our multi-omics approach revealed that the serine/threonine kinase liver-associated kinase B1 (LKB1) couples mitochondrial function to cytokine expression in T H 17 cells by regulating TCA cycle metabolism and transcriptional remodelling. Mitochondrial membrane disruption activates LKB1, which restrains IL-17 expression. LKB1 deletion restores IL-17 expression in T H 17 cells with disrupted mitochondrial membranes, rectifying aberrant TCA cycle glutamine flux, balancing NADH/NAD + and preventing 2-hydroxyglutarate production from the promiscuous activity of the serine biosynthesis enzyme phosphoglycerate dehydrogenase (PHGDH). These findings identify OPA1 as a major determinant of T H 17 cell function, and uncover LKB1 as a sensor linking mitochondrial cues to effector programmes in T H 17 cells. OPA1 regulates the formation of the distinct mitochondrial morphology observed in T helper 17 cells, which influences cytokine expression via LKB1.

Zwitterionic capsular polysaccharides (ZPS) of commensal bacteria are characterized by having both positive and negative charged substituents on each repeating unit of a highly repetitive structure that has an alpha-helix configuration. In this paper we look at the immune response of CD8(+) T cells to ZPSs. Intraperitoneal application of the ZPS Sp1 from Streptococcus pneumoniae serotype 1 induces CD8(+)CD28(-) T cells in the spleen and peritoneal cavity of WT mice. However, chemically modified Sp1 (mSp1) without the positive charge and resembling common negatively charged polysaccharides fails to induce CD8(+)CD28(-) T lymphocytes. The Sp1-induced CD8(+)CD28(-) T lymphocytes are CD122(low)CTLA-4(+)CD39(+). They synthesize IL-10 and TGF-beta. The Sp1-induced CD8(+)CD28(-) T cells exhibit immunosuppressive properties on CD4(+) T cells in vivo and in vitro. Experimental approaches to elucidate the mechanism of CD8(+) T cell activation by Sp1 demonstrate in a dimeric MHC class I-Ig model that Sp1 induces CD8(+) T cell activation by enhancing crosslinking of TCR. The expansion of CD8(+)CD28(-) T cells is independent, of direct antigen-presenting cell/T cell contact and, to the specificity of the T cell receptor (TCR). In CD8(+)CD28(-) T cells, Sp1 enhances Zap-70 phosphorylation and increasingly involves NF-kappaB which ultimately results in protection versus apoptosis and cell death and promotes survival and accumulation of the CD8(+)CD28(-) population. This is the first description of a naturally occurring bacterial antigen that is able to induce suppressive CD8(+)CD28(-) T lymphocytes in vivo and in vitro. The underlying mechanism of CD8(+) T cell activation appears to rely on enhanced TCR crosslinking. The data provides evidence that ZPS of commensal bacteria play an important role in peripheral tolerance mechanisms and the maintenance of the homeostasis of the immune system.

Sarcoidosis is a noninfectious, inflammatory multisystem disorder characterized by the idiopathic formation of granulomas. The pathogenesis of sarcoidosis remains only partially understood, although various clinical risk factors and extrinsic triggers have been identified, alongside a maintained Th1-mediated immune response. Clinically, sarcoidosis can present with specific manifestations associated with sarcoidal granulomas observable in histological examinations, as well as nonspecific manifestations. Histology is pivotal for diagnosis. In cases of cutaneous sarcoidosis, systemic involvement must be evaluated. Therapeutic approaches are tailored to the most affected organ. For cutaneous sarcoidosis, treatment options vary based on clinical findings and include local therapies as well as systemic interventions. These encompass corticosteroids and other immunosuppressive or immunomodulatory agents.