Abnormal Production of Pro- and Anti-Inflammatory Cytokines by Lupus Monocytes in Response to Apoptotic Cells
Andrade F (2011) Abnormal Production of Pro- and Anti-Inflammatory Cytokines by Lupus Monocytes in Response to
Apoptotic Cells. PLoS ONE 6(3): e17495. doi:10.1371/journal.pone.0017495
Abnormal Production of Pro- and Anti-Inflammatory Cytokines by Lupus Monocytes in Response to Apoptotic Cells
Sangeeta Sule 0
Antony Rosen 0
Michelle Petri 0
Ehtisham Akhter 0
Felipe Andrade 0
Pierre Bobe, Institut Jacques Monod, France
0 1 Department of Pediatrics, Johns Hopkins University School of Medicine , Baltimore , Maryland, United States of America, 2 Department of Medicine, Johns Hopkins University School of Medicine , Baltimore , Maryland, United States of America, 3 Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland , United States of America
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-a and TGF-b in response to apoptotic cells. Upon recognition of apoptotic material, monocytes from healthy controls showed prominent TGF-b secretion (mean 6 SD: 824.66144.3 pg/ml) and minimal TNF-a production (mean 6 SD: 32.662.1 pg/ml). In contrast, monocytes from SLE patients had prominent TNF-a production (mean 6 SD: 302.26337.5 pg/ml) and diminished TGF-b secretion (mean 6 SD: 685.96615.9 pg/ml), a difference that was statistically significant compared to normal monocytes (p#1026 for TNF-a secretion, and p = 0.0031 for TGF-b, 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-a 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.
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Funding: The Hopkins Lupus Cohort is supported by NIH grant AR43727 and the Johns Hopkins University School of Medicine General Clinical Research Center
(M01-RR00052). A.R. was supported by NIH grant DE12354. F.A is a Lowe Family Scholar in the Johns Hopkins Bayview Center for Innovative Medicine and was
supported by the Dana Foundation Scholars Program in Human Immunology. The funders had no role in study design, data collection and analysis, decision to
publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Systemic lupus erythematosus (SLE) is a multisystem
autoimmune disease characterized by an exuberant autoantibody
response to a wide variety of autoantigens. Disease is the result
of a cascade of events (induced by hormonal and environmental
factors) that occur on the background of an appropriate genetic
predisposition. In SLE, T and B-cell autoimmune responses result
in the generation of autoantibodies and immune complexes, along
with autoreactive T cells, which together cause pathology in
several target organs, including skin, blood vessels, lung and
kidney [1]. Defining the mechanisms underlying SLE initiation,
flares, and damage remains a high priority. The observation that
lupus autoantigens are selectively clustered in apoptotic surface
blebs initially focused attention on apoptosis as an important
pathway, upstream of inflammatory processes, which may be
relevant in initiating and propagating SLE [2,3].
In tissues, 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 [48]. Thus, the
early and efficient recognition and engulfment of apoptotic cells
has been proposed to be necessary to induce tolerance to
autoantigens. Although 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 [916], in human SLE, the possible
pathogenic consequences of an abnormal interaction between
apoptotic material and phagocytic cells remains unclear.
Persuasive but ind (...truncated)