Alpha 1 antitrypsin inhibits dendritic cell activation and attenuates nephritis in a mouse model of lupus

Ahmed S. Elshikha; Yuanqing Lu; Mong Jen Chen; Mohammad Akbar; Leilani Zeumer; Andrea Ritter; Hanaa Elghamry; Mahmoud A. Mahdi; Laurence Morel; Sihong Song

doi:10.1371/journal.pone.0156583

Alpha 1 antitrypsin inhibits dendritic cell activation and attenuates nephritis in a mouse model of lupus

Ahmed S. Elshikha, Yuanqing Lu, Mong Jen Chen, Mohammad Akbar, Leilani Zeumer, Andrea Ritter, Hanaa Elghamry, Mahmoud A. Mahdi, Laurence Morel, Sihong Song

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Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution and considerable mortality and morbidity. Although the pathogenesis of this disease remains elusive, over-reactive dendritic cells (DCs) play a critical role in the disease development. It has been shown that human alpha-1 antitrypsin (hAAT) has protective effects in type 1 diabetes and rheumatoid arthritis mouse models. In the present study, we tested the effect of AAT on DC differentiation and functions, as well as its protective effect in a lupusprone mouse model. We showed that hAAT treatment significantly inhibited LPS (TLR4 agonist) and CpG (TLR9 agonist) -induced bone-marrow (BM)-derived conventional and plasmacytoid DC (cDC and pDC) activation and reduced the production of inflammatory cytokines including IFN-I, TNF-α and IL-1β. In MRL/lpr mice, hAAT treatment significantly reduced BM-derived DC differentiation, serum autoantibody levels, and importantly attenuated renal pathology. Our results for the first time demonstrate that hAAT inhibits DC activation and function, and it also attenuates autoimmunity and renal damage in the MRL/lpr lupus model. These results imply that hAAT has a therapeutic potential for the treatment of SLE in humans.

Original language	English (US)
Article number	e0156583
Journal	PloS one
Volume	11
Issue number	5
DOIs	https://doi.org/10.1371/journal.pone.0156583
State	Published - May 2016
Externally published	Yes

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title = "Alpha 1 antitrypsin inhibits dendritic cell activation and attenuates nephritis in a mouse model of lupus",

abstract = "Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution and considerable mortality and morbidity. Although the pathogenesis of this disease remains elusive, over-reactive dendritic cells (DCs) play a critical role in the disease development. It has been shown that human alpha-1 antitrypsin (hAAT) has protective effects in type 1 diabetes and rheumatoid arthritis mouse models. In the present study, we tested the effect of AAT on DC differentiation and functions, as well as its protective effect in a lupusprone mouse model. We showed that hAAT treatment significantly inhibited LPS (TLR4 agonist) and CpG (TLR9 agonist) -induced bone-marrow (BM)-derived conventional and plasmacytoid DC (cDC and pDC) activation and reduced the production of inflammatory cytokines including IFN-I, TNF-α and IL-1β. In MRL/lpr mice, hAAT treatment significantly reduced BM-derived DC differentiation, serum autoantibody levels, and importantly attenuated renal pathology. Our results for the first time demonstrate that hAAT inhibits DC activation and function, and it also attenuates autoimmunity and renal damage in the MRL/lpr lupus model. These results imply that hAAT has a therapeutic potential for the treatment of SLE in humans.",

author = "Elshikha, {Ahmed S.} and Yuanqing Lu and Chen, {Mong Jen} and Mohammad Akbar and Leilani Zeumer and Andrea Ritter and Hanaa Elghamry and Mahdi, {Mahmoud A.} and Laurence Morel and Sihong Song",

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AU - Elshikha, Ahmed S.

AU - Lu, Yuanqing

AU - Chen, Mong Jen

AU - Akbar, Mohammad

AU - Zeumer, Leilani

AU - Ritter, Andrea

AU - Elghamry, Hanaa

AU - Mahdi, Mahmoud A.

AU - Morel, Laurence

AU - Song, Sihong

N1 - Publisher Copyright: © 2016 Elshikha et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2016/5

Y1 - 2016/5

N2 - Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution and considerable mortality and morbidity. Although the pathogenesis of this disease remains elusive, over-reactive dendritic cells (DCs) play a critical role in the disease development. It has been shown that human alpha-1 antitrypsin (hAAT) has protective effects in type 1 diabetes and rheumatoid arthritis mouse models. In the present study, we tested the effect of AAT on DC differentiation and functions, as well as its protective effect in a lupusprone mouse model. We showed that hAAT treatment significantly inhibited LPS (TLR4 agonist) and CpG (TLR9 agonist) -induced bone-marrow (BM)-derived conventional and plasmacytoid DC (cDC and pDC) activation and reduced the production of inflammatory cytokines including IFN-I, TNF-α and IL-1β. In MRL/lpr mice, hAAT treatment significantly reduced BM-derived DC differentiation, serum autoantibody levels, and importantly attenuated renal pathology. Our results for the first time demonstrate that hAAT inhibits DC activation and function, and it also attenuates autoimmunity and renal damage in the MRL/lpr lupus model. These results imply that hAAT has a therapeutic potential for the treatment of SLE in humans.

AB - Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution and considerable mortality and morbidity. Although the pathogenesis of this disease remains elusive, over-reactive dendritic cells (DCs) play a critical role in the disease development. It has been shown that human alpha-1 antitrypsin (hAAT) has protective effects in type 1 diabetes and rheumatoid arthritis mouse models. In the present study, we tested the effect of AAT on DC differentiation and functions, as well as its protective effect in a lupusprone mouse model. We showed that hAAT treatment significantly inhibited LPS (TLR4 agonist) and CpG (TLR9 agonist) -induced bone-marrow (BM)-derived conventional and plasmacytoid DC (cDC and pDC) activation and reduced the production of inflammatory cytokines including IFN-I, TNF-α and IL-1β. In MRL/lpr mice, hAAT treatment significantly reduced BM-derived DC differentiation, serum autoantibody levels, and importantly attenuated renal pathology. Our results for the first time demonstrate that hAAT inhibits DC activation and function, and it also attenuates autoimmunity and renal damage in the MRL/lpr lupus model. These results imply that hAAT has a therapeutic potential for the treatment of SLE in humans.

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Alpha 1 antitrypsin inhibits dendritic cell activation and attenuates nephritis in a mouse model of lupus

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