@article{KoenigerKuerten2017,
  author    = {Koeniger, Tobias and Kuerten, Stefanie},
  title     = {Splitting the "unsplittable": Dissecting resident and infiltrating macrophages in experimental autoimmune encephalomyelitis},
  series = {International Journal of Molecular Sciences},
  volume    = {18},
  journal   = {International Journal of Molecular Sciences},
  number    = {10},
  issn      = {1422-0067},
  doi       = {10.3390/ijms18102072},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285067},
  year      = {2017},
  abstract  = {Macrophages predominate the inflammatory landscape within multiple sclerosis (MS) lesions, not only regarding cellularity but also with respect to the diverse functions this cell fraction provides during disease progression and remission. Researchers have been well aware of the fact that the macrophage pool during central nervous system (CNS) autoimmunity consists of a mixture of myeloid cells. Yet, separating these populations to define their unique contribution to disease pathology has long been challenging due to their similar marker expression. Sophisticated lineage tracing approaches as well as comprehensive transcriptome analysis have elevated our insight into macrophage biology to a new level enabling scientists to dissect the roles of resident (microglia and non-parenchymal macrophages) and infiltrating macrophages with unprecedented precision. To do so in an accurate way, researchers have to know their toolbox, which has been filled with diverse, discriminating approaches from decades of studying neuroinflammation in animal models. Every method has its own strengths and weaknesses, which will be addressed in this review. The focus will be on tools to manipulate and/or identify different macrophage subgroups within the injured murine CNS.},
  language  = {en}
}
@article{SpitzelWagnerBreyeretal.2022,
  author    = {Spitzel, Marlene and Wagner, Elise and Breyer, Maximilian and Henniger, Dorothea and Bayin, Mehtap and Hofmann, Lukas and Mauceri, Daniela and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan},
  title     = {Dysregulation of immune response mediators and pain-related ion channels is associated with pain-like behavior in the GLA KO mouse model of Fabry disease},
  series = {Cells},
  volume    = {11},
  journal   = {Cells},
  number    = {11},
  issn      = {2073-4409},
  doi       = {10.3390/cells11111730},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-275186},
  year      = {2022},
  abstract  = {Fabry disease (FD) is a rare life-threatening disorder caused by deficiency of the alpha-galactosidase A (GLA) enzyme with a characteristic pain phenotype. Impaired GLA production or function leads to the accumulation of the cell membrane compound globotriaosylceramide (Gb3) in the neurons of the dorsal root ganglia (DRG) of FD patients. Applying immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT PCR) analysis on DRG tissue of the GLA knockout (KO) mouse model of FD, we address the question of how Gb3 accumulation may contribute to FD pain and focus on the immune system and pain-associated ion channel gene expression. We show a higher Gb3 load in the DRG of young (<6 months) (p < 0.01) and old (≥12 months) (p < 0.001) GLA KO mice compared to old wildtype (WT) littermates, and an overall suppressed immune response in the DRG of old GLA KO mice, represented by a reduced number of CD206\(^+\) macrophages (p < 0.01) and lower gene expression levels of the inflammation-associated targets interleukin(IL)1b (p < 0.05), IL10 (p < 0.001), glial fibrillary acidic protein (GFAP) (p < 0.05), and leucine rich alpha-2-glycoprotein 1 (LRG1) (p < 0.01) in the DRG of old GLA KO mice compared to old WT. Dysregulation of immune-related genes may be linked to lower gene expression levels of the pain-associated ion channels calcium-activated potassium channel 3.1 (KCa3.1) and transient receptor potential ankyrin 1 channel (TRPA1). Ion channel expression might further be disturbed by impaired sphingolipid recruitment mediated via the lipid raft marker flotillin-1 (FLOT1). This impairment is represented by an increased number of FLOT1\(^+\) DRG neurons with a membranous expression pattern in old GLA KO mice compared to young GLA KO, young WT, and old WT mice (p < 0.001 each). Further, we provide evidence for aberrant behavior of GLA KO mice, which might be linked to dysregulated ion channel gene expression levels and disturbed FLOT1 distribution patterns. Behavioral testing revealed mechanical hypersensitivity in young (p < 0.01) and old (p < 0.001) GLA KO mice compared to WT, heat hypersensitivity in young GLA KO mice (p < 0.001) compared to WT, age-dependent heat hyposensitivity in old GLA KO mice (p < 0.001) compared to young GLA KO mice, and cold hyposensitivity in young (p < 0.001) and old (p < 0.001) GLA KO mice compared to WT, which well reflects the clinical phenotype observed in FD patients.},
  language  = {en}
}
@phdthesis{Yuan2023,
  author    = {Yuan, Xidi},
  title     = {Aging and inflammation in the peripheral nervous system},
  doi       = {10.25972/OPUS-23737},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237378},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Aging is known to be a risk factor for structural abnormalities and functional decline in the nervous system. Characterizing age-related changes is important to identify putative pathways to overcome deleterious effects and improve life quality for the elderly. In this study, the peripheral nervous system of 24-month-old aged C57BL/6 mice has been investigated and compared to 12-month-old adult mice. Aged mice showed pathological alterations in their peripheral nerves similar to nerve biopsies from elderly human individuals, with nerve fibers showing demyelination and axonal damage. Such changes were lacking in nerves of adult 12-month-old mice and adult, non-aged humans. Moreover, neuromuscular junctions of 24-month-old mice showed increased denervation compared to adult mice. These alterations were accompanied by elevated numbers of macrophages in the peripheral nerves of aged mice. The neuroinflammatory conditions were associated with impaired myelin integrity and with a decline of nerve conduction properties and muscle strength in aged mice. To determine the pathological impact of macrophages in the aging mice, macrophage depletion was performed in mice by oral administration of CSF-1R specific kinase (c-FMS) inhibitor PLX5622 (300 mg/kg body weight), which reduced the number of macrophages in the peripheral nerves by 70\%. The treated mice showed attenuated demyelination, less muscle denervation and preserved muscle strength. This indicates that macrophage-driven inflammation in the peripheral nerves is partially responsible for the age-related neuropathy in mice. Based on previous observations that systemic inflammation can accelerate disease progression in mouse models of neurodegenerative diseases, it was hypothesized that systemic inflammation can exacerbate the peripheral neuropathy found in aged mice. To investigate this hypothesis, aged C57BL/6 mice were intraperitoneally injected with a single dose of lipopolysaccharide (LPS; 500 μg/kg body weight) to induce systemic inflammation by mimicking bacterial infection, mostly via activation of Toll-like receptors (TLRs). Altered endoneurial macrophage activation, highlighted by Trem2 downregulation, was found in LPS injected aged mice one month after injection. This was accompanied by a so far rarely observed form of axonal perturbation, i.e., the occurrence of "dark axons" characterized by a damaged cytoskeleton and an increased overall electron density of the axoplasm. At the same time, however, LPS injection reduced demyelination and muscle denervation in aged mice. Interestingly, TREM2 deficiency in aged mice led to similar changes to LPS injection. This suggests that LPS injection likely mitigates aging-related demyelination and muscle denervation via Trem2 downregulation. Taken together, this study reveals the role of macrophage-driven inflammation as a pathogenic mediator in age-related peripheral neuropathy, and that targeting macrophages might be an option to mitigate peripheral neuropathies in aging individuals. Furthermore, this study shows that systemic inflammation may be an ambivalent modifier of age-related nerve damage, leading to a distinct type of axonal perturbation, but in addition to functionally counteracting, dampened demyelination and muscle denervation. Translationally, it is plausible to assume that tipping the balance of macrophage polarization to one direction or the other may determine the functional outcome in the aging peripheral nervous system of the elderly.},
  subject      = {Maus},
  language  = {en}
}
@article{BeheraJainGangulietal.2022,
  author    = {Behera, Ananyaashree and Jain, Preeti and Ganguli, Geetanjali and Biswas, Mainak and Padhi, Avinash and Pattanaik, Kali Prasad and Nayak, Barsa and Erg{\"u}n, S{\"u}leyman and Hagens, Kristine and Redinger, Natalja and Saqib, Mohd and Mishra, Bibhuti B. and Schaible, Ulrich E. and Karnati, Srikanth and Sonawane, Avinash},
  title     = {Mycobacterium tuberculosis acetyltransferase suppresses oxidative stress by inducing peroxisome formation in macrophages},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {5},
  issn      = {1422-0067},
  doi       = {10.3390/ijms23052584},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284080},
  year      = {2022},
  abstract  = {Mycobacterium tuberculosis (Mtb) inhibits host oxidative stress responses facilitating its survival in macrophages; however, the underlying molecular mechanisms are poorly understood. Here, we identified a Mtb acetyltransferase (Rv3034c) as a novel counter actor of macrophage oxidative stress responses by inducing peroxisome formation. An inducible Rv3034c deletion mutant of Mtb failed to induce peroxisome biogenesis, expression of the peroxisomal β-oxidation pathway intermediates (ACOX1, ACAA1, MFP2) in macrophages, resulting in reduced intracellular survival compared to the parental strain. This reduced virulence phenotype was rescued by repletion of Rv3034c. Peroxisome induction depended on the interaction between Rv3034c and the macrophage mannose receptor (MR). Interaction between Rv3034c and MR induced expression of the peroxisomal biogenesis proteins PEX5p, PEX13p, PEX14p, PEX11β, PEX19p, the peroxisomal membrane lipid transporter ABCD3, and catalase. Expression of PEX14p and ABCD3 was also enhanced in lungs from Mtb aerosol-infected mice. This is the first report that peroxisome-mediated control of ROS balance is essential for innate immune responses to Mtb but can be counteracted by the mycobacterial acetyltransferase Rv3034c. Thus, peroxisomes represent interesting targets for host-directed therapeutics to tuberculosis.},
  language  = {en}
}
@article{KleefeldtUpcinBoemmeletal.2022,
  author    = {Kleefeldt, Florian and Upcin, Berin and B{\"o}mmel, Heike and Schulz, Christian and Eckner, Georg and Allmanritter, Jan and Bauer, Jochen and Braunger, Barbara and Rueckschloss, Uwe and Erg{\"u}n, S{\"u}leyman},
  title     = {Bone marrow-independent adventitial macrophage progenitor cells contribute to angiogenesis},
  series = {Cell Death \& Disease},
  volume    = {13},
  journal   = {Cell Death \& Disease},
  number    = {3},
  doi       = {10.1038/s41419-022-04605-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-299724},
  year      = {2022},
  abstract  = {Pathological angiogenesis promotes tumor growth, metastasis, and atherosclerotic plaque rupture. Macrophages are key players in these processes. However, whether these macrophages differentiate from bone marrow-derived monocytes or from local vascular wall-resident stem and progenitor cells (VW-SCs) is an unresolved issue of angiogenesis. To answer this question, we analyzed vascular sprouting and alterations in aortic cell populations in mouse aortic ring assays (ARA). ARA culture leads to the generation of large numbers of macrophages, especially within the aortic adventitia. Using immunohistochemical fate-mapping and genetic in vivo-labeling approaches we show that 60\% of these macrophages differentiate from bone marrow-independent Ly6c\(^{+}\)/Sca-1\(^{+}\) adventitial progenitor cells. Analysis of the NCX\(^{-/-}\) mouse model that genetically lacks embryonic circulation and yolk sac perfusion indicates that at least some of those progenitor cells arise yolk sac-independent. Macrophages represent the main source of VEGF in ARA that vice versa promotes the generation of additional macrophages thereby creating a pro-angiogenetic feedforward loop. Additionally, macrophage-derived VEGF activates CD34\(^{+}\) progenitor cells within the adventitial vasculogenic zone to differentiate into CD31\(^{+}\) endothelial cells. Consequently, depletion of macrophages and VEGFR2 antagonism drastically reduce vascular sprouting activity in ARA. In summary, we show that angiogenic activation induces differentiation of macrophages from bone marrow-derived as well as from bone marrow-independent VW-SCs. The latter ones are at least partially yolk sac-independent, too. Those VW-SC-derived macrophages critically contribute to angiogenesis, making them an attractive target to interfere with pathological angiogenesis in cancer and atherosclerosis as well as with regenerative angiogenesis in ischemic cardiovascular disorders.},
  language  = {en}
}
@article{SaintFleurLominyMausVaethetal.2018,
  author    = {Saint Fleur-Lominy, Shella and Maus, Mate and Vaeth, Martin and Lange, Ingo and Zee, Isabelle and Suh, David and Liu, Cynthia and Wu, Xiaojun and Tikhonova, Anastasia and Aifantis, Iannis and Feske, Stefan},
  title     = {STIM1 and STIM2 Mediate Cancer-Induced Inflammation in T Cell Acute Lymphoblastic Leukemia},
  series = {Cell Reports},
  volume    = {24},
  journal   = {Cell Reports},
  number    = {11},
  doi       = {10.1016/j.celrep.2018.08.030},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227259},
  pages     = {3045-3060},
  year      = {2018},
  abstract  = {T cell acute lymphoblastic leukemia (T-ALL) is commonly associated with activating mutations in the NOTCH1 pathway. Recent reports have shown a link between NOTCH1 signaling and intracellular Ca2+ homeostasis in T-ALL. Here, we investigate the role of store-operated Ca2+ entry (SOCE) mediated by the Ca2+ channel ORAI1 and its activators STIM1 and STIM2 in T-ALL. Deletion of STIM1 and STIM2 in leukemic cells abolishes SOCE and significantly prolongs the survival of mice in a NOTCH1-dependent model of T-ALL. The survival advantage is unrelated to the leukemic cell burden but is associated with the SOCE-dependent ability of malignant T lymphoblasts to cause inflammation in leukemia-infiltrated organs. Mice with STIM1/STIM2-deficient T-ALL show a markedly reduced necroinflammatory response in leukemia-infiltrated organs and downregulation of signaling pathways previously linked to cancer-induced inflammation. Our study shows that leukemic T lymphoblasts cause inflammation of leukemia-infiltrated organs that is dependent on SOCE.},
  language  = {en}
}
@article{PelosiFioreDiMatteoetal.2021,
  author    = {Pelosi, Andrea and Fiore, Piera Filomena and Di Matteo, Sabina and Veneziani, Irene and Caruana, Ignazio and Ebert, Stefan and Munari, Enrico and Moretta, Lorenzo and Maggi, Enrico and Azzarone, Bruno},
  title     = {Pediatric tumors-mediated inhibitory effect on NK cells: the case of neuroblastoma and Wilms' tumors},
  series = {Cancers},
  volume    = {13},
  journal   = {Cancers},
  number    = {10},
  issn      = {2072-6694},
  doi       = {10.3390/cancers13102374},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239615},
  year      = {2021},
  abstract  = {Natural killer (NK) cells play a key role in the control of cancer development, progression and metastatic dissemination. However, tumor cells develop an array of strategies capable of impairing the activation and function of the immune system, including NK cells. In this context, a major event is represented by the establishment of an immunosuppressive tumor microenvironment (TME) composed of stromal cells, myeloid-derived suppressor cells, tumor-associated macrophages, regulatory T cells and cancer cells themselves. The different immunoregulatory cells infiltrating the TME, through the release of several immunosuppressive molecules or by cell-to-cell interactions, cause an impairment of the recruitment of NK cells and other lymphocytes with effector functions. The different mechanisms by which stromal and tumor cells impair NK cell function have been particularly explored in adult solid tumors and, in less depth, investigated and discussed in a pediatric setting. In this review, we will compare pediatric and adult solid malignancies concerning the respective mechanisms of NK cell inhibition, highlighting novel key data in neuroblastoma and Wilms' tumor, two of the most frequent pediatric extracranial solid tumors. Indeed, both tumors are characterized by the presence of stromal cells acting through the release of immunosuppressive molecules. In addition, specific tumor cell subsets inhibit NK cell cytotoxic function by cell-to-cell contact mechanisms likely controlled by the transcriptional coactivator TAZ. These findings could lead to a more performant diagnostic approach and to the development of novel immunotherapeutic strategies targeting the identified cellular and molecular targets.},
  language  = {en}
}
@article{FioreVaccaTuminoetal.2021,
  author    = {Fiore, Piera Filomena and Vacca, Paola and Tumino, Nicola and Besi, Francesca and Pelosi, Andrea and Munari, Enrico and Marconi, Marcella and Caruana, Ignazio and Pistoia, Vito and Moretta, Lorenzo and Azzarone, Bruno},
  title     = {Wilms' tumor primary cells display potent immunoregulatory properties on NK cells and macrophages},
  series = {Cancers},
  volume    = {13},
  journal   = {Cancers},
  number    = {2},
  issn      = {2072-6694},
  doi       = {10.3390/cancers13020224},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222981},
  year      = {2021},
  abstract  = {The immune response plays a crucial defensive role in cancer growth and metastasis and is a promising target in different tumors. The role of the immune system in Wilm's Tumor (WT), a common pediatric renal malignancy, is still to be explored. The characterization of the immune environment in WT could allow the identification of new therapeutic strategies for targeting possible inhibitory mechanisms and/or lowering toxicity of the current treatments. In this study, we stabilized four WT primary cultures expressing either a blastematous (CD56\(^+\)/CD133\(^-\)) or an epithelial (CD56\(^-\)/CD133\(^+\)) phenotype and investigated their interactions with innate immune cells, namely NK cells and monocytes. We show that cytokine-activated NK cells efficiently kill WT cells. However, after co-culture with WT primary cells, NK cells displayed an impaired cytotoxic activity, decreased production of IFNγ and expression of CD107a, DNAM-1 and NKp30. Analysis of the effects of the interaction between WT cells and monocytes revealed their polarization towards alternatively activated macrophages (M2) that, in turn, further impaired NK cell functions. In conclusion, we show that both WT blastematous and epithelial components may contribute directly and indirectly to a tumor immunosuppressive microenvironment that is likely to play a role in tumor progression.},
  language  = {en}
}
@article{BenKraiemSauerNorwigetal.2021,
  author    = {Ben-Kraiem, Adel and Sauer, Reine-Solange and Norwig, Carla and Popp, Maria and Bettenhausen, Anna-Lena and Atalla, Mariam Sobhy and Brack, Alexander and Blum, Robert and Doppler, Kathrin and Rittner, Heike Lydia},
  title     = {Selective blood-nerve barrier leakiness with claudin-1 and vessel-associated macrophage loss in diabetic polyneuropathy},
  series = {Journal of Molecular Medicine},
  volume    = {99},
  journal   = {Journal of Molecular Medicine},
  number    = {9},
  doi       = {10.1007/s00109-021-02091-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265237},
  pages     = {1237-1250},
  year      = {2021},
  abstract  = {Diabetic polyneuropathy (DPN) is the most common complication in diabetes and can be painful in up to 26\% of all diabetic patients. Peripheral nerves are shielded by the blood-nerve barrier (BNB) consisting of the perineurium and endoneurial vessels. So far, there are conflicting results regarding the role and function of the BNB in the pathophysiology of DPN. In this study, we analyzed the spatiotemporal tight junction protein profile, barrier permeability, and vessel-associated macrophages in Wistar rats with streptozotocin-induced DPN. In these rats, mechanical hypersensitivity developed after 2 weeks and loss of motor function after 8 weeks, while the BNB and the blood-DRG barrier were leakier for small, but not for large molecules after 8 weeks only. The blood-spinal cord barrier remained sealed throughout the observation period. No gross changes in tight junction protein or cytokine expression were observed in all barriers to blood. However, expression of Cldn1 mRNA in perineurium was specifically downregulated in conjunction with weaker vessel-associated macrophage shielding of the BNB. Our results underline the role of specific tight junction proteins and BNB breakdown in DPN maintenance and differentiate DPN from traumatic nerve injury. Targeting claudins and sealing the BNB could stabilize pain and prevent further nerve damage.},
  language  = {en}
}
@article{RymaTylekLiebscheretal.2021,
  author    = {Ryma, Matthias and Tylek, Tina and Liebscher, Julia and Blum, Carina and Fernandez, Robin and B{\"o}hm, Christoph and Kastenm{\"u}ller, Wolfgang and Gasteiger, Georg and Groll, J{\"u}rgen},
  title     = {Translation of collagen ultrastructure to biomaterial fabrication for material-independent but highly efficient topographic immunomodulation},
  series = {Advanced materials},
  volume    = {33},
  journal   = {Advanced materials},
  number    = {33},
  doi       = {10.1002/adma.202101228},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-256381},
  year      = {2021},
  abstract  = {Supplement-free induction of cellular differentiation and polarization solely through the topography of materials is an auspicious strategy but has so far significantly lagged behind the efficiency and intensity of media-supplementation-based protocols. Consistent with the idea that 3D structural motifs in the extracellular matrix possess immunomodulatory capacity as part of the natural healing process, it is found in this study that human-monocyte-derived macrophages show a strong M2a-like prohealing polarization when cultured on type I rat-tail collagen fibers but not on collagen I films. Therefore, it is hypothesized that highly aligned nanofibrils also of synthetic polymers, if packed into larger bundles in 3D topographical biomimetic similarity to native collagen I, would induce a localized macrophage polarization. For the automated fabrication of such bundles in a 3D printing manner, the strategy of "melt electrofibrillation" is pioneered by the integration of flow-directed polymer phase separation into melt electrowriting and subsequent selective dissolution of the matrix polymer postprocessing. This process yields nanofiber bundles with a remarkable structural similarity to native collagen I fibers, particularly for medical-grade poly(ε-caprolactone). These biomimetic fibrillar structures indeed induce a pronounced elongation of human-monocyte-derived macrophages and unprecedentedly trigger their M2-like polarization similar in efficacy as interleukin-4 treatment.},
  language  = {en}
}