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 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

42 Scopus citations

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Rosetti, F., Tsuboi, N., Chen, K., Nishi, H., Ernandez, T., Sethi, S., Croce, K., Stavrakis, G., Alcocer-Varela, J., Gómez-Martin, D., Van Rooijen, N., Kyttaris, V. C., Lichtman, A. H., Tsokos, G. C., & Mayadas, T. N. (2012). Human lupus serum induces neutrophil-mediated organ damage in mice that is enabled by Mac-1 deficiency. Journal of Immunology, 189(7), 3714-3723. https://doi.org/10.4049/jimmunol.1201594