IL-17 producing CD4+ T cells mediate accelerated ischemia/reperfusion-induced injury in autoimmunity-prone mice

Edgerton, C.; Crispín, José C.; Moratz, Chantal; Bettelli, Estelle; Oukka, Mohamed; Simovic, Milomir O.; Zacharia, Athina; Egan, Ryan; Chen, Jie; Lucca, Jurandir J. Dalle; Juang, Yuang Taung; Tsokos, George C.

doi:10.1016/j.clim.2008.09.019

Cited by 81 publications

(79 citation statements)

References 41 publications

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“…For example, a hypoxic condition augments cytokine production in CD4 T cells (36). CD4 T cell cytokines, such as IL-6, IL-17, TNF-a, and IFN-g, contribute to the pathogenesis of IRI of kidney, liver, lung, and intestine (15,(37)(38)(39)(40). The CD4 T cell cytokines are also known to regulate the expression of other soluble mediators of inflammation and the function of leukocytes, including monocytes and neutrophils.…”

Section: Discussionmentioning

confidence: 99%

Netrin-1 Regulates Th1/Th2/Th17 Cytokine Production and Inflammation through UNC5B Receptor and Protects Kidney against Ischemia–Reperfusion Injury

Tadagavadi

Wang

Ramesh

2010

The Journal of Immunology

114

139

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Section: Discussionmentioning

confidence: 99%

Netrin-1 Regulates Th1/Th2/Th17 Cytokine Production and Inflammation through UNC5B Receptor and Protects Kidney against Ischemia–Reperfusion Injury

Tadagavadi

Wang

Ramesh

2010

The Journal of Immunology

114

139

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“…10,12 IL-17A was originally implicated in several disease processes, such as encephalomyelitis 13 ; psoriasis 14 ; atherosclerosis 15 ; hypertension 16 ; viral myocarditis; dilated cardiomyopathy 17 ; and ischemia-reperfusion injury of brain, kidney, and intestine. [18][19][20] Subsequent studies, however, have disputed a pathogenic role for IL-17 in many of these diseases [21][22][23][24] and provided data to the contrary showing that IL-17 can favorably modulate inflammation. Moreover, an IL-17A neutralizing antibody therapy developed to treat arthritis exacerbated the disease process, further pointing toward a protective role of this cytokine in certain disease states.…”

mentioning

confidence: 99%

Low-Dose IL-17 Therapy Prevents and Reverses Diabetic Nephropathy, Metabolic Syndrome, and Associated Organ Fibrosis

Mohamed

Jayakumar

Chen

et al. 2016

Journal of the American Society of Nephrology

106

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Diabetes is the leading cause of kidney failure, accounting for .45% of new cases of dialysis. Diabetic nephropathy is characterized by inflammation, fibrosis, and oxidant stress, pathologic features that are shared by many other chronic inflammatory diseases. The cytokine IL-17A was initially implicated as a mediator of chronic inflammatory diseases, but recent studies dispute these findings and suggest that IL-17A can favorably modulate inflammation. Here, we examined the role of IL-17A in diabetic nephropathy. We observed that IL-17A levels in plasma and urine were reduced in patients with advanced diabetic nephropathy. Type 1 diabetic mice that are genetically deficient in IL-17A developed more severe nephropathy, whereas administration of low-dose IL-17A prevented diabetic nephropathy in models of type 1 and type 2 diabetes. Moreover, IL-17A administration effectively treated, prevented, and reversed established nephropathy in genetic models of diabetes. Protective effects were also observed after administration of IL-17F but not IL-17C or IL-17E. Notably, tubular epithelial cell-specific overexpression of IL-17A was sufficient to suppress diabetic nephropathy. Mechanistically, IL-17A administration suppressed phosphorylation of signal transducer and activator of transcription 3, a central mediator of fibrosis, upregulated anti-inflammatory microglia/macrophage WAP domain protein in an AMP-activated protein kinasedependent manner and favorably modulated renal oxidative stress and AMP-activated protein kinase activation. Administration of recombinant microglia/macrophage WAP domain protein suppressed diabetes-induced albuminuria and enhanced M2 marker expression. These observations suggest that the beneficial effects of IL-17 are isoform-specific and identify low-dose IL-17A administration as a promising therapeutic approach in diabetic kidney disease. CKDs such as diabetic nephropathy are a serious public health problem. In the United States, .20 million adults have CKD, and 20%-40% of patients with diabetes develop nephropathy. The financial burden of diabetes is estimated to be $245 billion per year in the United States alone, and the cost for diabetic nephropathy is estimated to be .$20 billion per year. While intensive insulin therapy and control of hypertension can delay the onset of diabetic nephropathy, 1-3 these therapies cannot reverse CKD once it has developed. Recently, feeding mice a strictly ketogenic diet (5% carbohydrate, 8% protein, 87% fat) reversed a mild form of nephropathy. 4 Although implementing such an extreme diet

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“…Many studies have shown that parasitemia and the subsequent potent pro-inflammatory response are essential for developing CM (Walther et al 2009). In a commonly used murine CM model, the Pb ANKA-infected C57BL/6 mice, the development of CM is associated with high levels of inflammatory mediators such as IFN-γ, TNF-α, and NO during infection (Hunt and Grau 2003;Engwerda et al 2005;Jain et al 2008;Edgerton et al 2009;). In agreement with these work, here we found that splenocytes producing pro-inflammatory mediators, such as IFN-γ-secreting Th1 cells and F4/80 + CD36 + cells, were both increased in spleen from Pb ANKA-infected mice treated with L-Arg.…”

Section: Discussionmentioning

confidence: 99%

L-Arginine Exacerbates Experimental Cerebral Malaria by Enhancing Pro-Inflammatory Responses

Feng

Chen³

et al. 2015

Tohoku J. Exp. Med.

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L-Arginine (L-Arg), the substrate for nitric oxide (NO) synthase, has been used to treat malaria to reverse endothelial dysfunction in adults. However, the safety and efficacy of L-Arg remains unknown in malaria patients under the age of five, who are at the greatest risk of developing cerebral malaria (CM), a severe malaria complication. Here, we tested effects of L-Arg treatment on the outcomes of CM using a mouse model. Experimental cerebral malaria (ECM) was induced in female C57BL/6 mice infected with Plasmodium berghei ANKA, and L-Arg was administrated either prophylactically or after parasite infection. ) in the spleen. The levels of pro-inflammatory cytokines, IFN-γ and TNF-α, in splenocyte cultures were also increased by L-Arg treatment. The above changes were accompanied with a rise in the number of dendritic cells (DCs) and an increase in their maturation. However, L-Arg did not affect the population of regulatory T cells or the level of IL-10 in the spleen. Taken together, these data suggest that L-Arg may enhance the Th1 immune response, which is essential for a protective response in uncomplicated malaria but could be lethal in CM patients. Therefore, the prophylactic use of L-Arg to treat CM, based on the assumption that restoring the bioavailability of endothelial NO improves the outcome of CM, may need to be reconsidered especially for children.

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IL-17 producing CD4+ T cells mediate accelerated ischemia/reperfusion-induced injury in autoimmunity-prone mice

Cited by 81 publications

References 41 publications

Netrin-1 Regulates Th1/Th2/Th17 Cytokine Production and Inflammation through UNC5B Receptor and Protects Kidney against Ischemia–Reperfusion Injury

Netrin-1 Regulates Th1/Th2/Th17 Cytokine Production and Inflammation through UNC5B Receptor and Protects Kidney against Ischemia–Reperfusion Injury

Low-Dose IL-17 Therapy Prevents and Reverses Diabetic Nephropathy, Metabolic Syndrome, and Associated Organ Fibrosis

L-Arginine Exacerbates Experimental Cerebral Malaria by Enhancing Pro-Inflammatory Responses

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