The CXCR1/2 Pathway: Involvement in Diabetes Pathophysiology and Potential Target for T1D Interventions

Citro, Antonio; Cantarelli, Elisa; Piemonti, Lorenzo

doi:10.1007/s11892-015-0638-x

Cited by 29 publications

(27 citation statements)

References 75 publications

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“…We demonstrated previously that inflammation is a critical determinant in the pathophysiology of DN (Awad et al ; You et al ). KC‐GRO/CXCL1 is a cytokine that plays an important role in leukocyte recruitment, and mediates inflammation in diabetes (Citro et al ). Kidney KC‐GRO/CXCL1 significantly increased in untreated Ins2 Akita mice compared to nondiabetic controls, an effect that was attenuated by oral l ‐homoarginine supplementation (Fig.…”

Section: Resultsmentioning

confidence: 99%

l ‐Homoarginine supplementation prevents diabetic kidney damage

et al. 2019

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l‐homoarginine is an endogenous, non‐proteinogenic amino acid that has emerged as a new player in health and disease. Specifically, low l‐homoarginine levels are associated with cardiovascular diseases, stroke, and reduced kidney function. However, the role of l‐homoarginine in the pathogenesis of diabetic nephropathy (DN) is not known. Experiments were conducted in 6‐week‐old Ins2Akita mice supplemented with l‐homoarginine via drinking water or mini osmotic pump for 12 weeks. Both plasma and kidney l‐homoarginine levels were significantly reduced in diabetic mice compared to nondiabetic controls. Untreated Ins2Akita mice showed significant increases in urinary albumin excretion, histological changes, glomerular macrophage recruitment, the inflammatory cytokine KC‐GRO/CXCL1, and urinary thiobarbituric acid reactive substances (TBARS) excretion as an indicator of oxidative stress, along with a significant reduction in kidney nitrate + nitrite levels compared to control mice at 18 weeks of age. In contrast, l‐homoarginine supplementation for 12 weeks in Ins2Akita mice, via either drinking water or mini osmotic pump, significantly reduced albuminuria, renal histological changes, glomerular macrophage recruitment, KC‐GRO/CXCL1 levels, urinary TBARS excretion, and largely restored kidney nitrate + nitrite levels. These data demonstrate that l‐homoarginine supplementation attenuates specific features of DN in mice and could be a potential new therapeutic tool for treating diabetic patients.

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Section: Resultsmentioning

confidence: 99%

l ‐Homoarginine supplementation prevents diabetic kidney damage

et al. 2019

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“…Regarding CXCR1, it has always been found to function in combination with CXCR2. The CXCR1/2 complex has been detected on neutrophils, macrophages, and lymphocytes, and these cell types are critical in inflammatory processes and autoimmune diseases [50,87,88]. Inhibition of CXCR1/2 has been shown to prevent islet damage due to immune disorders, and this inhibition also promotes autoimmune throditis [50].…”

Section: Discussionmentioning

confidence: 99%

“…The CXCR1/2 complex has been detected on neutrophils, macrophages, and lymphocytes, and these cell types are critical in inflammatory processes and autoimmune diseases [50,87,88]. Inhibition of CXCR1/2 has been shown to prevent islet damage due to immune disorders, and this inhibition also promotes autoimmune throditis [50]. Alternatively, the CXCR1/CXCL8 axis has been associated with the accumulation of NK cells in the liver of patients with primary biliary disease, thereby contributing to the pathological development of this disease [89].…”

Section: Discussionmentioning

confidence: 99%

Abnormal Expression of Long Noncoding RNAs in Primary Immune Thrombocytopenia: A Microarray Related Study

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Long noncoding RNAs (lncRNAs) are important regulators of biological processes and they contribute to the pathological developments of various diseases, including autoimmune diseases. To gain the further understanding, we estimate the expression of lncRNAs in primary immune thrombocytopenia (ITP). Methods: In this study, microarray studies were performed to characterize expression profiles of various lncRNAs and mRNAs in blood samples collected from ITP patients. Quantitative real-time PCR (qRT-PCR) was performed to confirm the results, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and gene ontology analysis were used to provide functional annotations, co-expression network construction (CNC) analysis was made to reveal the relations between lncRNAs and their targeted genes. Results: A total of 1177 and 632 lncRNAs were significantly up-regulated or down-regulated, respectively, in “newly diagnosed ITP” patients versus healthy individuals. In addition, 1182 genes and 737 genes were up-regulated or down-regulated, respectively, in “chronic recurrent ITP” patients versus healthy individuals. In a KEGG analysis, “TNF signaling pathway-Homo sapiens (human)” was a key result. In a gene ontology analysis, “Granulocyte macrophage colony-stimulating factor production (GO: 0032604, ontology: Biological process, P = 1.69577E-05)” and “coreceptor activity (GO: 0015026, ontology: molecular function, P = 4.67594E-06)” were the two most critical results. Data from qRT-PCR and receiver operating characteristic curves further demonstrated that ENST00000440492, ENST00000528366, NR_038920, and ENST00000552576 can efficiently distinguish different stages of ITP, especially NR_038920 and ENST00000528366. In a CNC analysis, four lncRNAs were emphasized, and NR_038920 and ENST00000528366 were both associated with proteins with important roles in autoimmune diseases. Conclusions: These results suggest that lncRNAs act through targeted genes to mediate their functions and to mediate their functions and affect the pathogenesis of ITP.

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“…elucidating the agents potential in a less immunogenic syngeneic transplant setting. 9,19 As well, this is the subject of an ongoing international randomized controlled blinded trial.…”

Section: Discussionmentioning

confidence: 99%

“…The CXCR1/2 receptors are G-protein receptors on neutrophils (PMN), normally activated by the chemotactic factor CXCL-8 (IL-8), which subsequently induces T cell and NK cell migration to the site of inflammation. [5][6][7][8][9] During the acute innate immune response the neutrophils are first responders. 8 By inducing conformational changes in the PMN receptors, reparixin renders them inactive, thereby inhibiting proinflammatory cytokine production and leukocyte infiltration.…”

Section: Introductionmentioning

confidence: 99%

Reparixin, a CXCR1/2 inhibitor in islet allotransplantation

Pawlick

Wink

Pepper

et al. 2016

Islets

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Quality of life in Type 1 diabetic patients may be improved with islet transplantation, but lifelong immunosuppression is required to prevent rejection. Allo-immune response is a key player in graft dysfunction and although the adaptive immune response is well characterized, the effect of the innate immune reaction after transplantation is only recently becoming appreciated. In this study, we address how the innate response affects long-term outcomes in a murine islet allotransplant model. CTLA-4 Ig treatment is known to significantly prolong kidney subcapsular islet allograft survival and enhance glucose tolerance. The combination of CTLA-4 Ig with reparixin, which blocks against inflammatory neutrophil infiltration, yielded no long-term graft survival in an intrahepatic allotransplant model but had similar long-term graft survival in the kidney subcapsular model. Seven days after transplant, serum blood IFN-g levels were significantly lower in the CTLA-4 Ig with reparixin treatment group compared to controls. IL-12p70 cytokine levels were increased with combination treatment, a positive modulation of the inflammatory response to the allograft. Furthermore, KC GRO, also known as CXCL1, was decreased in serum 7 d after transplant. Histologically, we found that immune cell infiltrate, CD4C and CD8C T cell populations along with both CXCR1C and CXCR2C cell populations were decreased within the CTLA-4 Ig and reparixin islet transplant graft. Overall these data provide insight into the down regulation of T-cell recruitment by CTLA-4 Ig and decreased neutrophil activation and recruitment with reparixin after long-term islet graft survival.

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The CXCR1/2 Pathway: Involvement in Diabetes Pathophysiology and Potential Target for T1D Interventions

Cited by 29 publications

References 75 publications

l ‐Homoarginine supplementation prevents diabetic kidney damage

l ‐Homoarginine supplementation prevents diabetic kidney damage

Abnormal Expression of Long Noncoding RNAs in Primary Immune Thrombocytopenia: A Microarray Related Study

Reparixin, a CXCR1/2 inhibitor in islet allotransplantation

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