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, multi-organ 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.

CD11b activation suppresses TLR-dependent inflammation and autoimmunity in systemic lupus erythematosus

“…14, 17-21, and reviewed in ref. 22), including increased tissue infiltration of leukocytes and immune-mediated injury in lupus-prone mice (19,20). These data further suggest that CD11b plays a protective role in SLE.…”

Pristane-Induced Granulocyte Recruitment Promotes Phenotypic Conversion of Macrophages and Protects against Diffuse Pulmonary Hemorrhage in Mac-1 Deficiency

“…Previous studies have suggested that Mac-1 has contextdependent inhibitory and activating functions for recruitment of leukocytes to the site of inflammation. Mac-1 deficiency resulted in increased Neu accumulation and enhanced tissue injury in mouse models of rheumatoid arthritis, reverse Arthus reaction, and lupus nephritis (13,44,45), but resulted in decreased Neu accumulation and attenuated inflammation in models of acute anti-GBM, thrombotic glomerulonephritis, and bullous pemphigoid (13,46). In the current study, we observed significantly enhanced initial recruitment of Neu and Eos into the peritoneal cavity in Mac-1 mutant animals; however, the kinetics of subsequent accumulation differed in these granulocytes, as Neu generally decreased whereas Eos levels remained high until day 2.…”

“…1E, 2C). A similar inhibitory function of Mac-1 in Neu recruitment has been described in the reverse passive Arthus reaction, in which Mac-1-deficient Neu showed slow rolling velocity and increased chemoattractantinduced adhesion of Neu (13). To determine whether pristanemediated extravasation of Neu and Eos from peripheral circulation into the peritoneal cavity was an active process that involved chemoattractant receptor signaling (29), we pretreated Mac-1 2/2 and WT mice with an i.v.…”

“…Mac-1-deficient mice on a C57BL/6 background (Mac-1 2/2 ) were obtained from Dr. Tanya N. Mayadas (13), and wild-type (WT) mice were purchased from Chubu Kagaku Shizai (Nagoya, Japan). Mice were maintained in a virus-and Ab-free facility at the animal housing facility at Nagoya University Graduate School of Medicine.…”

“…Animal studies using gene-targeted mice have reported ambivalent roles for Mac-1: promotion of innate immune-mediated inflammation by supporting Neu recruitment, interaction with platelets, triggering of cytotoxic functions, and cooperation with other receptors such as CD14, Dectin, and FcgRs (10-13), whereas protective immunomodulation via inhibition of IFN-a and TLR signaling or T cell proliferation (14,15). Recent animal studies of SLE have indicated that Mac-1 deficiency promotes target organ damage via regulation of FcgRIIA-mediated Neu recruitment or the maintenance of autoreactive B cell tolerance (13,16). Moreover, several human genome-wide association studies have reported that Mac-1 may be associated with susceptibility to SLE, and that mutations within the CD11b locus may be a risk factor related to autoantibody production and severe manifestations of SLE (17,18).…”