Abnormal Production of Pro- and Anti-Inflammatory Cytokines by Lupus Monocytes in Response to Apoptotic Cells

PLOS ONE, Mar 2011

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.

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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. - 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)


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Sangeeta Sule, Antony Rosen, Michelle Petri, Ehtisham Akhter, Felipe Andrade. Abnormal Production of Pro- and Anti-Inflammatory Cytokines by Lupus Monocytes in Response to Apoptotic Cells, PLOS ONE, 2011, Volume 6, Issue 3, DOI: 10.1371/journal.pone.0017495