C5a receptor 1 promotes autoimmunity, neutrophil dysfunction and injury in experimental anti-myeloperoxidase glomerulonephritis

Jonathan Dick, Poh Yi Gan, Sharon L. Ford, Dragana Odobasic, Maliha A. Alikhan, Sven H. Loosen, Pam Hall, Clare L. Westhorpe, Anqi Li, Joshua D. Ooi, Trent M. Woodruff, Charles R. Mackay, A. Richard Kitching, Michael J. Hickey, Stephen R. Holdsworth

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The prospects for complement-targeted therapy in ANCA-associated vasculitis have been enhanced by a recent clinical trial in which C5a receptor 1 (C5aR1) inhibition safely replaced glucocorticoids in induction treatment. C5aR1 primes neutrophils for activation by anti-neutrophil cytoplasmic antibody (ANCA) and is therefore required in models of glomerulonephritis induced by anti-myeloperoxidase antibody. Although humoral and cellular autoimmunity play essential roles in ANCA-associated vasculitis, a role for C5aR1 in these responses has not been described. Here, we use murine models to dissect the role of C5aR1 in the generation of anti-myeloperoxidase autoimmunity and the effector responses resulting in renal injury. The genetic absence or pharmacological inhibition of C5aR1 results in reduced autoimmunity to myeloperoxidase with an attenuated Th1 response, increased Foxp3+ regulatory T cells and reduction in generation of myeloperoxidase-ANCA. These changes are mediated by C5aR1 on dendritic cells, which promotes activation, and thus myeloperoxidase autoimmunity and glomerulonephritis. We also use renal intravital microscopy to determine the effect of C5aR1 inhibition on ANCA induced neutrophil dysfunction. We found that myeloperoxidase-ANCA induce neutrophil retention and reactive oxygen species burst within glomerular capillaries. These pathological behaviors are abrogated by C5aR1 inhibition. Thus, C5aR1 inhibition ameliorates both autoimmunity and intra-renal neutrophil activation in ANCA-associated vasculitis.

Original languageEnglish
Pages (from-to)615-625
Number of pages11
JournalKidney International
Volume93
Issue number3
DOIs
Publication statusPublished - 1 Mar 2018

Keywords

  • ANCA
  • autoimmunity
  • C5aR1
  • complement
  • glomerulonephritis
  • vasculitis

Cite this

@article{8c263d7cb2a04096a56d62e9b9f81511,
title = "C5a receptor 1 promotes autoimmunity, neutrophil dysfunction and injury in experimental anti-myeloperoxidase glomerulonephritis",
abstract = "The prospects for complement-targeted therapy in ANCA-associated vasculitis have been enhanced by a recent clinical trial in which C5a receptor 1 (C5aR1) inhibition safely replaced glucocorticoids in induction treatment. C5aR1 primes neutrophils for activation by anti-neutrophil cytoplasmic antibody (ANCA) and is therefore required in models of glomerulonephritis induced by anti-myeloperoxidase antibody. Although humoral and cellular autoimmunity play essential roles in ANCA-associated vasculitis, a role for C5aR1 in these responses has not been described. Here, we use murine models to dissect the role of C5aR1 in the generation of anti-myeloperoxidase autoimmunity and the effector responses resulting in renal injury. The genetic absence or pharmacological inhibition of C5aR1 results in reduced autoimmunity to myeloperoxidase with an attenuated Th1 response, increased Foxp3+ regulatory T cells and reduction in generation of myeloperoxidase-ANCA. These changes are mediated by C5aR1 on dendritic cells, which promotes activation, and thus myeloperoxidase autoimmunity and glomerulonephritis. We also use renal intravital microscopy to determine the effect of C5aR1 inhibition on ANCA induced neutrophil dysfunction. We found that myeloperoxidase-ANCA induce neutrophil retention and reactive oxygen species burst within glomerular capillaries. These pathological behaviors are abrogated by C5aR1 inhibition. Thus, C5aR1 inhibition ameliorates both autoimmunity and intra-renal neutrophil activation in ANCA-associated vasculitis.",
keywords = "ANCA, autoimmunity, C5aR1, complement, glomerulonephritis, vasculitis",
author = "Jonathan Dick and Gan, {Poh Yi} and Ford, {Sharon L.} and Dragana Odobasic and Alikhan, {Maliha A.} and Loosen, {Sven H.} and Pam Hall and Westhorpe, {Clare L.} and Anqi Li and Ooi, {Joshua D.} and Woodruff, {Trent M.} and Mackay, {Charles R.} and Kitching, {A. Richard} and Hickey, {Michael J.} and Holdsworth, {Stephen R.}",
year = "2018",
month = "3",
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doi = "10.1016/j.kint.2017.09.018",
language = "English",
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journal = "Kidney International",
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C5a receptor 1 promotes autoimmunity, neutrophil dysfunction and injury in experimental anti-myeloperoxidase glomerulonephritis. / Dick, Jonathan; Gan, Poh Yi; Ford, Sharon L.; Odobasic, Dragana; Alikhan, Maliha A.; Loosen, Sven H.; Hall, Pam; Westhorpe, Clare L.; Li, Anqi; Ooi, Joshua D.; Woodruff, Trent M.; Mackay, Charles R.; Kitching, A. Richard; Hickey, Michael J.; Holdsworth, Stephen R.

In: Kidney International, Vol. 93, No. 3, 01.03.2018, p. 615-625.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - C5a receptor 1 promotes autoimmunity, neutrophil dysfunction and injury in experimental anti-myeloperoxidase glomerulonephritis

AU - Dick, Jonathan

AU - Gan, Poh Yi

AU - Ford, Sharon L.

AU - Odobasic, Dragana

AU - Alikhan, Maliha A.

AU - Loosen, Sven H.

AU - Hall, Pam

AU - Westhorpe, Clare L.

AU - Li, Anqi

AU - Ooi, Joshua D.

AU - Woodruff, Trent M.

AU - Mackay, Charles R.

AU - Kitching, A. Richard

AU - Hickey, Michael J.

AU - Holdsworth, Stephen R.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - The prospects for complement-targeted therapy in ANCA-associated vasculitis have been enhanced by a recent clinical trial in which C5a receptor 1 (C5aR1) inhibition safely replaced glucocorticoids in induction treatment. C5aR1 primes neutrophils for activation by anti-neutrophil cytoplasmic antibody (ANCA) and is therefore required in models of glomerulonephritis induced by anti-myeloperoxidase antibody. Although humoral and cellular autoimmunity play essential roles in ANCA-associated vasculitis, a role for C5aR1 in these responses has not been described. Here, we use murine models to dissect the role of C5aR1 in the generation of anti-myeloperoxidase autoimmunity and the effector responses resulting in renal injury. The genetic absence or pharmacological inhibition of C5aR1 results in reduced autoimmunity to myeloperoxidase with an attenuated Th1 response, increased Foxp3+ regulatory T cells and reduction in generation of myeloperoxidase-ANCA. These changes are mediated by C5aR1 on dendritic cells, which promotes activation, and thus myeloperoxidase autoimmunity and glomerulonephritis. We also use renal intravital microscopy to determine the effect of C5aR1 inhibition on ANCA induced neutrophil dysfunction. We found that myeloperoxidase-ANCA induce neutrophil retention and reactive oxygen species burst within glomerular capillaries. These pathological behaviors are abrogated by C5aR1 inhibition. Thus, C5aR1 inhibition ameliorates both autoimmunity and intra-renal neutrophil activation in ANCA-associated vasculitis.

AB - The prospects for complement-targeted therapy in ANCA-associated vasculitis have been enhanced by a recent clinical trial in which C5a receptor 1 (C5aR1) inhibition safely replaced glucocorticoids in induction treatment. C5aR1 primes neutrophils for activation by anti-neutrophil cytoplasmic antibody (ANCA) and is therefore required in models of glomerulonephritis induced by anti-myeloperoxidase antibody. Although humoral and cellular autoimmunity play essential roles in ANCA-associated vasculitis, a role for C5aR1 in these responses has not been described. Here, we use murine models to dissect the role of C5aR1 in the generation of anti-myeloperoxidase autoimmunity and the effector responses resulting in renal injury. The genetic absence or pharmacological inhibition of C5aR1 results in reduced autoimmunity to myeloperoxidase with an attenuated Th1 response, increased Foxp3+ regulatory T cells and reduction in generation of myeloperoxidase-ANCA. These changes are mediated by C5aR1 on dendritic cells, which promotes activation, and thus myeloperoxidase autoimmunity and glomerulonephritis. We also use renal intravital microscopy to determine the effect of C5aR1 inhibition on ANCA induced neutrophil dysfunction. We found that myeloperoxidase-ANCA induce neutrophil retention and reactive oxygen species burst within glomerular capillaries. These pathological behaviors are abrogated by C5aR1 inhibition. Thus, C5aR1 inhibition ameliorates both autoimmunity and intra-renal neutrophil activation in ANCA-associated vasculitis.

KW - ANCA

KW - autoimmunity

KW - C5aR1

KW - complement

KW - glomerulonephritis

KW - vasculitis

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U2 - 10.1016/j.kint.2017.09.018

DO - 10.1016/j.kint.2017.09.018

M3 - Article

VL - 93

SP - 615

EP - 625

JO - Kidney International

JF - Kidney International

SN - 0085-2538

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