Angela Colmone

Vitamin B12 contributes to acne by affecting the skin microbiota

Vitamin B12 stimulates the transcription of genes that promote inflammation from the skin microbiota. Vitamin B12 supplements lead to the development of acne. Kang et al. showed that transcriptional changes in the skin microbiota contribute to vitamin B12–induced acne. Supplementing patients with vitamin B12 reduced the expression of genes involved in vitamin B12 synthesis in Propionibacterium acnes and altered the transcriptome of the skin microbiota, resulting in the production of inflammation-inducing porphyrins by the bacteria. These studies demonstrate a clear link between changes in the skin microbiome and disease pathology. D. Kang, B. Shi, M. C. Erfe, N. Craft, H. Li, Vitamin B12 modulates the transcriptome of the skin microbiota in acne pathogenesis. Sci. Transl. Med. 7, 293ra103 (2015). [Abstract]

Dawn of new graft-versus-host disease therapies

Transcriptomic profiling of primate T cells during acute graft-versus-host disease reveals signaling pathways that can be inhibited to ameliorate disease. Hematopoietic stem cell transplant (HCT) is a common therapy for patients with damaged bone marrow or immunodeficiencies. However, HCT is not without risk: If the donor is not a perfect match to the recipient, immune cells derived from the graft can attack their new home. Furlan et al. examined the gene expression profile of nonhuman primate T cells during acute graft-versus-host disease (GVHD). The transcriptomics signatures specific for alloreactive T cells identified pathways altered during acute GVHD that could serve as therapeutic targets. Detailed analysis of one putative target, aurora kinase A, demonstrated that pharmacologic inhibition improved survival in a mouse model of GVHD. S. N. Furlan, B. Watkins, V. Tkachev, R. Flynn, S. Cooley, S. Ramakrishnan, K. Singh, C. Giver, K. Hamby, L. Stempora, A. Garrett, J. Chen, K. M. Betz, C. G. K. Ziegler, G. K. Tharp, S. E. Bosinger, D. E. L. Promislow, J. S. Miller, E. K. Waller, B. R. Blazar, L. S. Kean, Transcriptome analysis of GVHD reveals aurora kinase A as a targetable pathway for disease prevention. Sci. Transl. Med. 7, 315ra191 (2015). [Abstract]

Anti-inflammatory strategies reach for the SKY

The peptide SKY disrupts the interaction between the peptide HNP1 and the chemokine CCL5 on platelets, thereby reducing inflammation. Inflammation aids the body’s response to infection or injury but can cause damage if excessive or unresolved. Alard et al. examined how two early inflammatory mediators—neutrophils and platelets—cooperate to enhance inflammation. They found that human neutrophil peptide 1 (HNP1), which is secreted from neutrophils, forms a heteromer with the chemokine CCL5 on platelets, resulting in enhanced monocyte adhesion and an increase in inflammation. Disrupting this interaction with a peptide (SKY) decreased inflammation and blocked monocyte recruitment in a mouse model of myocardial infarction. If these results hold true in humans, they could form the basis for a new specific therapeutic in inflammation-associated diseases. J.-E. Alard, A. Ortega-Gomez, K. Wichapong, D. Bongiovanni, M. Horckmans, R. T. A. Megens, G. Leoni, B. Ferraro, J. Rossaint, N. Paulin, J. Ng, H. Ippel, D. Suylen, R. Hinkel, X. Blanchet, F. Gaillard, M. D’Amico, P. von Hundelshausen, A. Zarbock, C. Scheiermann, T. M. Hackeng, S. Steffens, C. Kupatt, G. A. F. Nicolaes, C. Weber, O. Soehnlein, Recruitment of classical monocytes can be inhibited by disturbing heteromers of neutrophil HNP1 and platelet CCL5. Sci. Transl. Med. 7, 317ra196 (2015). [Abstract]

Switching off arthritis

Targeting joint-lining fibroblast-like synoviocytes reduces the severity of arthritis. In patients with rheumatoid arthritis (RA), joint-lining cells—fibroblast-like synoviocytes (FLS)—become activated and contribute to inflammation, as well as cartilage and bone destruction. FLS have the receptor protein tyrosine phosphatase RPTPσ. In neurons, the interaction of RPTPσ with different proteoglycans either inhibits or promotes axonal growth, a phenomenon called the “proteoglycan switch.” Doody et al. found that FLS also responded to proteoglycans and that an RPTPσ decoy protein blocked this switch in human cells and decreased FLS invasiveness and severity of arthritis in a mouse model of RA. Targeting this proteoglycan switch may add another option when treating patients with RA. K. M. Doody, S. M. Stanford, C. Sacchetti, M. N. D. Svensson, C. H. Coles, N. Mitakidis, W. B. Kiosses, B. Bartok, C. Fos, E. Cory, R. L. Sah, R. Liu-Bryan, D. L. Boyle, H. A. Arnett, T. Mustelin, M. Corr, J. D. Esko, M. L. Tremblay, G. S. Firestein, A. R. Aricescu, N. Bottini, Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy. Sci. Transl. Med. 7, 288ra76 (2015). [Abstract]

Normalizing immune cell metabolism treats lupus

Systemic lupus erythematosus is associated with enhanced CD4+ T cell metabolism and can be reversed by metabolic modulators. Systemic lupus erythematosus (SLE) is an autoimmune disease where the immune system attacks normal, healthy tissues. CD4+ T cells are critical to SLE pathogenesis, but it has remained unclear if metabolism in these cells contributes to disease. Now, Yin et al. report that two metabolic pathways—glycolysis and mitochondrial oxidative metabolism—are elevated in cells from SLE patients as well as in mouse models of disease. What’s more, inhibitors of these pathways currently in the clinic—2-deoxy-D-glucose and metformin—normalized T cell metabolism and decreased markers of SLE in animal models as well as in cells from SLE patients. These data suggest that inhibiting both glycolysis and mitochondrial metabolism could be a new therapeutic strategy for treating SLE. Y. Yin, S.-C. Choi, Z. Xu, D. J. Perry, H. Seay, B. P. Croker, E. S. Sobel, T. M. Brusko, L. Morel, Normalization of CD4+ T cell metabolism reverses lupus. Sci. Transl. Med. 7, 274ra18 (2015). [Abstract] M. M. Mehta, N. S. Chandel, Targeting metabolism for lupus therapy. Sci. Transl. Med. 7, 274fs5 (2015). [Abstract]

Rethinking myelin-reactive T cells in multiple sclerosis

Myelin-reactive T cells from patients with multiple sclerosis are proinflammatory. In patients with multiple sclerosis (MS), the ability of nerves to carry messages is disrupted because of damage to their insulating cover—the myelin sheath. This damage is thought to be caused by the body’s own immune cells; however, myelin-reactive immune cells are found in comparable numbers in MS patients and healthy controls. Cao et al. report that myelin-reactive T cells from MS patients are functionally different than those from healthy controls; cells from MS patients are more proinflammatory, whereas cells from controls secrete more of the immunoregulatory cytokine interleukin-10. Furthermore, the myelin-reactive T cells from the MS patients exhibited a distinct pathogenic gene expression profile and share a similar transcriptomic profile to pathological T cells isolated from mice with experimental autoimmune encephalitis. These data suggest that functional differences in these cells may contribute to the development of disease. Y. Cao, B. A. Goods, K. Raddassi, G. T. Nepom, W. W. Kwok, J. C. Love, D. A. Hafler, Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis. Sci. Transl. Med. 7, 287ra74 (2015). [Abstract]

Immunotherapy: Reduce, reuse, recycle

IL-2Rα sustains IL-2 immunotherapy response after cytokine withdrawal by recycling and cell surface reservoirs. Interleukin-2 (IL-2) is a cytokine used in the clinic to boost immune cell responses to cancer. The related cytokine IL-15 also stimulates the proliferation of effector T cells but, unlike IL-2, does not stimulate proliferation of regulatory T cells. Su et al. demonstrate that, although IL-15 may be effective in lymphopenic patients, IL-2 therapy may be needed in patients who retain immune cells, where T cells compete for available cytokine. In isolated T cells, addition of IL-2, but not IL-15, resulted in sustained signaling even after the cytokine was removed, because IL-2 remained bound to the high-affinity receptor subunit IL-2Rα, which does not bind IL-15. IL-2Rα forms a cell surface reservoir of IL-2 and also enabled recycling of IL-2 back to the cell surface, thereby increasing the efficiency of signaling by limited quantities of cytokine. E. W. Su, C. J. Moore, S. Suriano, C. B. Johnson, N. Songalia, A. Patterson, D. J. Neitzke, K. Andrijauskaite, E. Garrett-Mayer, S. Mehrotra, C. M. Paulos, A. L. Doedens, A. W. Goldrath, Z. Li, D. J. Cole, M. P. Rubinstein, IL-2Rα mediates temporal regulation of IL-2 signaling and enhances immunotherapy. Sci. Transl. Med. 7, 311ra170 (2015). [Abstract]

Lowering the bar for autoimmunity

Genetic variants associated with multiple sclerosis result in increased NF-κB signaling in CD4 T cells and a decreased threshold for activation. In patients with autoimmune diseases, such as multiple sclerosis, immune cells attack the tissues that they are supposed to protect. However, it remains unclear why these self-targeted cells become activated in some individuals and not in others. Housley et al. showed that at least some multiple sclerosis patients have genetic variants that result in increased NF-κB signaling after stimulation with the cytokine TNFα. These variants, in effect, lower the activation threshold of CD4+ T cells, making them more responsive to inflammation and thus more likely to contribute to autoimmunity. Patients with these variants may be good candidates for therapies that block either NF-κB signaling or inflammatory cytokines. W. J. Housley, S. D. Fernandez, K. Vera, S. R. Murikinati, J. Grutzendler, N. Cuerdon, L. Glick, P. L. De Jager, M. Mitrovic, C. Cotsapas, D. A. Hafler, Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli. Sci. Transl. Med. 7, 291ra93 (2015). [Abstract]

Taking antidepressants to heart

GRK2 inhibition with paroxetine improves cardiac function independent of its central nervous system effects. Drug repurposing—extending currently Food and Drug Administration (FDA)–approved drugs to treat additional diseases—has both economic and safety advantages over new drug development. The selective serotonin reuptake inhibitor (SSRI) paroxetine, which is used as an antidepressant, selectively inhibits G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptor kinase 2 (GRK2), a kinase thought to contribute to heart failure progression. Schumacher et al. report that paroxetine blocked or reversed heart damage after myocardial infarction in a mouse model. These cardiac effects were distinct from the SSRI activity of paroxetine and were further enhanced by the concurrent treatment with β-blockers, clinically used drugs that inhibit β-adrenergic receptor signaling. Thus, paroxetine may be useful for treating heart failure. S. M. Schumacher, E. Gao, W. Zhu, X. Chen, J. K. Chuprun, A. M. Feldman, J. J. G. Tesmer, W. J. Koch, Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction. Sci. Transl. Med. 7, 277ra31 (2015). [Abstract]

Eclipsing multiple sclerosis

GM-CSF–producing B cells contribute to multiple sclerosis pathogenesis and the therapeutic action of B cell depletion. Through an unknown mechanism, B cell depletion therapy (BCDT) limits inflammation in some cases of multiple sclerosis (MS). Li et al. reported that a subset of B cells that produce the cytokine granulocyte macrophage–colony stimulating factor (GM-CSF) contributes to MS pathogenesis. Compared with healthy controls, MS patients had a higher number of these cells, and in vitro these cells promoted proinflammatory myeloid responses. Moreover, these GM-CSF–releasing B cells inhibited the generation of interleukin-10 (IL-10)–producing regulatory B cells, which are thought to be protective in disease. After BCDT, the ratio of GM-CSF– to IL-10–producing B cells was normalized, suggesting that BCDT may work in part by decreasing the number of pathogenic GM-CSF–producing B cells. R. Li, A. Rezk, Y. Miyazaki, E. Hilgenberg, H. Touill, P. Shen, C. S. Moore, L. Michel, F. Althekair, S. Rajasekharan, J. L. Gommerman, A. Prat, S. Fillatreau, A. Bar-Or, on behalf of the Canadian B cells in, MS Team, Proinflammatory GM-CSF–producing B cells in multiple sclerosis and B cell depletion therapy. Sci. Transl. Med. 7, 310ra166 (2015). [Abstract]