Human lupus serum induces neutrophil-mediated organ damage in mice that is enabled by Mac-1 deficiency

Florencia Rosetti, Naotake Tsuboi, Kan Chen, Hiroshi Nishi, Thomas Ernandez, Sanjeev M Sethi, Kevin Croce, George Stavrakis, Jorge Alcocer-Varela, Diana Gómez-Martin, Nico Van Rooijen, Vasileios C. Kyttaris, Andrew H. Lichtman, George C. Tsokos, Tanya N. Mayadas

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Systemic lupus erythematosus (SLE) is a chronic, multiorgan inflammatory autoimmune disorder associated with high levels of circulating autoantibodies and immune complexes. We report that passive transfer of human SLE sera into mice expressing the uniquely human FcγRIIA and FcγRIIIB on neutrophils induces lupus nephritis and in some cases arthritis only when the mice additionally lack the CD18 integrin, Mac-1. The prevailing view is that Mac-1 on macrophages is responsible for immune complex clearance. However, disease permitted by the absence of Mac-1 is not related to enhanced renal immune complex deposition or in situ C1q/C3 complement activation and proceeds even in the absence of macrophages. Instead, disease is associated with increased FcγRIIA-induced neutrophil accumulation that is enabled by Mac-1 deficiency. Intravital microscopy in the cremasteric vasculature reveals that Mac-1 mitigates FcγRIIA-dependent neutrophil recruitment in response to deposited immune complexes. Our results provide direct evidence that human SLE immune complexes are pathogenic, demonstrate that neutrophils are primary mediators of end organ damage in a novel humanized lupus mouse model, and identify Mac-1 regulation of FcγRIIA-mediated neutrophil recruitment as a key step in development of target organ damage. Copyright

Original languageEnglish (US)
Pages (from-to)3714-3723
Number of pages10
JournalJournal of Immunology
Volume189
Issue number7
DOIs
StatePublished - Oct 1 2012

Fingerprint

Antigen-Antibody Complex
Neutrophils
Systemic Lupus Erythematosus
Serum
Neutrophil Infiltration
Macrophages
Lupus Nephritis
Complement Activation
Integrins
Autoantibodies
Arthritis
Kidney

ASJC Scopus subject areas

  • Immunology

Cite this

Human lupus serum induces neutrophil-mediated organ damage in mice that is enabled by Mac-1 deficiency. / Rosetti, Florencia; Tsuboi, Naotake; Chen, Kan; Nishi, Hiroshi; Ernandez, Thomas; Sethi, Sanjeev M; Croce, Kevin; Stavrakis, George; Alcocer-Varela, Jorge; Gómez-Martin, Diana; Van Rooijen, Nico; Kyttaris, Vasileios C.; Lichtman, Andrew H.; Tsokos, George C.; Mayadas, Tanya N.

In: Journal of Immunology, Vol. 189, No. 7, 01.10.2012, p. 3714-3723.

Research output: Contribution to journalArticle

Rosetti, F, Tsuboi, N, Chen, K, Nishi, H, Ernandez, T, Sethi, SM, Croce, K, Stavrakis, G, Alcocer-Varela, J, Gómez-Martin, D, Van Rooijen, N, Kyttaris, VC, Lichtman, AH, Tsokos, GC & Mayadas, TN 2012, 'Human lupus serum induces neutrophil-mediated organ damage in mice that is enabled by Mac-1 deficiency', Journal of Immunology, vol. 189, no. 7, pp. 3714-3723. https://doi.org/10.4049/jimmunol.1201594
Rosetti, Florencia ; Tsuboi, Naotake ; Chen, Kan ; Nishi, Hiroshi ; Ernandez, Thomas ; Sethi, Sanjeev M ; Croce, Kevin ; Stavrakis, George ; Alcocer-Varela, Jorge ; Gómez-Martin, Diana ; Van Rooijen, Nico ; Kyttaris, Vasileios C. ; Lichtman, Andrew H. ; Tsokos, George C. ; Mayadas, Tanya N. / Human lupus serum induces neutrophil-mediated organ damage in mice that is enabled by Mac-1 deficiency. In: Journal of Immunology. 2012 ; Vol. 189, No. 7. pp. 3714-3723.
@article{c227a3cbb4fb45caa2ff1ca242801b3f,
title = "Human lupus serum induces neutrophil-mediated organ damage in mice that is enabled by Mac-1 deficiency",
abstract = "Systemic lupus erythematosus (SLE) is a chronic, multiorgan inflammatory autoimmune disorder associated with high levels of circulating autoantibodies and immune complexes. We report that passive transfer of human SLE sera into mice expressing the uniquely human FcγRIIA and FcγRIIIB on neutrophils induces lupus nephritis and in some cases arthritis only when the mice additionally lack the CD18 integrin, Mac-1. The prevailing view is that Mac-1 on macrophages is responsible for immune complex clearance. However, disease permitted by the absence of Mac-1 is not related to enhanced renal immune complex deposition or in situ C1q/C3 complement activation and proceeds even in the absence of macrophages. Instead, disease is associated with increased FcγRIIA-induced neutrophil accumulation that is enabled by Mac-1 deficiency. Intravital microscopy in the cremasteric vasculature reveals that Mac-1 mitigates FcγRIIA-dependent neutrophil recruitment in response to deposited immune complexes. Our results provide direct evidence that human SLE immune complexes are pathogenic, demonstrate that neutrophils are primary mediators of end organ damage in a novel humanized lupus mouse model, and identify Mac-1 regulation of FcγRIIA-mediated neutrophil recruitment as a key step in development of target organ damage. Copyright",
author = "Florencia Rosetti and Naotake Tsuboi and Kan Chen and Hiroshi Nishi and Thomas Ernandez and Sethi, {Sanjeev M} and Kevin Croce and George Stavrakis and Jorge Alcocer-Varela and Diana G{\'o}mez-Martin and {Van Rooijen}, Nico and Kyttaris, {Vasileios C.} and Lichtman, {Andrew H.} and Tsokos, {George C.} and Mayadas, {Tanya N.}",
year = "2012",
month = "10",
day = "1",
doi = "10.4049/jimmunol.1201594",
language = "English (US)",
volume = "189",
pages = "3714--3723",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "7",

}

TY - JOUR

T1 - Human lupus serum induces neutrophil-mediated organ damage in mice that is enabled by Mac-1 deficiency

AU - Rosetti, Florencia

AU - Tsuboi, Naotake

AU - Chen, Kan

AU - Nishi, Hiroshi

AU - Ernandez, Thomas

AU - Sethi, Sanjeev M

AU - Croce, Kevin

AU - Stavrakis, George

AU - Alcocer-Varela, Jorge

AU - Gómez-Martin, Diana

AU - Van Rooijen, Nico

AU - Kyttaris, Vasileios C.

AU - Lichtman, Andrew H.

AU - Tsokos, George C.

AU - Mayadas, Tanya N.

PY - 2012/10/1

Y1 - 2012/10/1

N2 - Systemic lupus erythematosus (SLE) is a chronic, multiorgan inflammatory autoimmune disorder associated with high levels of circulating autoantibodies and immune complexes. We report that passive transfer of human SLE sera into mice expressing the uniquely human FcγRIIA and FcγRIIIB on neutrophils induces lupus nephritis and in some cases arthritis only when the mice additionally lack the CD18 integrin, Mac-1. The prevailing view is that Mac-1 on macrophages is responsible for immune complex clearance. However, disease permitted by the absence of Mac-1 is not related to enhanced renal immune complex deposition or in situ C1q/C3 complement activation and proceeds even in the absence of macrophages. Instead, disease is associated with increased FcγRIIA-induced neutrophil accumulation that is enabled by Mac-1 deficiency. Intravital microscopy in the cremasteric vasculature reveals that Mac-1 mitigates FcγRIIA-dependent neutrophil recruitment in response to deposited immune complexes. Our results provide direct evidence that human SLE immune complexes are pathogenic, demonstrate that neutrophils are primary mediators of end organ damage in a novel humanized lupus mouse model, and identify Mac-1 regulation of FcγRIIA-mediated neutrophil recruitment as a key step in development of target organ damage. Copyright

AB - Systemic lupus erythematosus (SLE) is a chronic, multiorgan inflammatory autoimmune disorder associated with high levels of circulating autoantibodies and immune complexes. We report that passive transfer of human SLE sera into mice expressing the uniquely human FcγRIIA and FcγRIIIB on neutrophils induces lupus nephritis and in some cases arthritis only when the mice additionally lack the CD18 integrin, Mac-1. The prevailing view is that Mac-1 on macrophages is responsible for immune complex clearance. However, disease permitted by the absence of Mac-1 is not related to enhanced renal immune complex deposition or in situ C1q/C3 complement activation and proceeds even in the absence of macrophages. Instead, disease is associated with increased FcγRIIA-induced neutrophil accumulation that is enabled by Mac-1 deficiency. Intravital microscopy in the cremasteric vasculature reveals that Mac-1 mitigates FcγRIIA-dependent neutrophil recruitment in response to deposited immune complexes. Our results provide direct evidence that human SLE immune complexes are pathogenic, demonstrate that neutrophils are primary mediators of end organ damage in a novel humanized lupus mouse model, and identify Mac-1 regulation of FcγRIIA-mediated neutrophil recruitment as a key step in development of target organ damage. Copyright

UR - http://www.scopus.com/inward/record.url?scp=84866561476&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866561476&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1201594

DO - 10.4049/jimmunol.1201594

M3 - Article

C2 - 22933624

AN - SCOPUS:84866561476

VL - 189

SP - 3714

EP - 3723

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 7

ER -