Abstract
Monocytes are a key component of the innate immune system involved in the regulation of the adaptive immune response. Previous studies have focused on apoptotic cell clearance abnormalities in systemic lupus erythematosus (SLE) monocytes. However, whether SLE monocytes might express unique patterns of cytokine secretion in response to apoptotic cells is still unknown. Here, we used monocytes from healthy controls and SLE patients to evaluate the production of TNF-α and TGF-β in response to apoptotic cells. Upon recognition of apoptotic material, monocytes from healthy controls showed prominent TGF-β secretion (mean ± SD: 824.6±144.3 pg/ml) and minimal TNF-α production (mean ± SD: 32.6±2.1 pg/ml). In contrast, monocytes from SLE patients had prominent TNF-α production (mean ± SD: 302.2±337.5 pg/ml) and diminished TGF-β secretion (mean ± SD: 685.9±615.9 pg/ml), a difference that was statistically significant compared to normal monocytes (p≤10−6 for TNF-α secretion, and p = 0.0031 for TGF-β, respectively). Interestingly, the unique cytokine response by SLE monocytes was independent of their phagocytic clearance efficiency, opsonizing autoantibodies and disease activity. We further showed that nucleic acids from apoptotic cells play important role in the induction of TNF-α by lupus monocytes. Together, these observations suggest that, in addition to potential clearance defects, monocytes from SLE patients have an abnormal balance in the secretion of anti- and pro-inflammatory cytokines in response to apoptotic cells. Since the abnormal cytokine response to apoptotic material in SLE is not related to disease activity and opsonizing autoantibodies, it is possible that this response might be an intrinsic property of lupus monocytes. The studies focus attention on toll-like receptors (TLRs) and their downstream pathways as mediators of this response.
Highlights
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by an exuberant autoantibody response to a wide variety of autoantigens
Apoptotic cells are rapidly engulfed by macrophages in the early phase of apoptotic cell death, and this uptake is associated with secretion of anti-inflammatory cytokines, such as TGF-b and IL-10, decreased secretion of IL-12 and TNF-a and failure to upregulate co-stimulatory molecules [4,5,6,7,8]
To determine whether SLE patients have unique patterns of cytokine secretion in response to apoptotic material, we studied a large number of patients (47 patients) and quantified the production of TGF-b and TNF-a using a highly standardized and reproducible assay in which control or SLE monocytes are co-incubated in the absence or presence of dying cells in which apoptosis was induced by ultraviolet B (UVB)-irradiation
Summary
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by an exuberant autoantibody response to a wide variety of autoantigens. Cumulative evidence from experimental animal models has demonstrated that adequate apoptotic cell clearance plays a role in mediating tolerance to apoptotic cells and preventing autoimmunity [9,10,11,12,13,14,15,16], in human SLE, the possible pathogenic consequences of an abnormal interaction between apoptotic material and phagocytic cells remains unclear. Persuasive but indirect evidence suggests that patients with SLE have impaired phagocytosis of apoptotic cells [17,18,19,20], but whether the phagocytic defect is intrinsic to their macrophages, or acquired as result of the abnormal inflammatory lupus environment (i.e. cytokines and/or opsonizing molecules) is still unclear [21,22]. Whether SLE phagocytes might have unique patterns of cytokine secretion in response to apoptotic cells has still to be defined
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