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
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
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U2 - 10.4049/jimmunol.1201594
DO - 10.4049/jimmunol.1201594
M3 - Article
C2 - 22933624
AN - SCOPUS:84866561476
SN - 0022-1767
VL - 189
SP - 3714
EP - 3723
JO - Journal of Immunology
JF - Journal of Immunology
IS - 7
ER -