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Complement protein C1q bound to apoptotic cells suppresses human macrophage and dendritic cell-mediated Th17 and Th1
Elizabeth V Clarke1, Brian M Weist2, Craig M Walsh1
1Department of Molecular Biology and Biochemistry, Institute for Immunology, University of California-Irvine, Irvine, California, USA; and.
Insights
Complement protein C1q deficiency causes lupus (SLE) by impairing phagocyte clearance of dying cells. C1q-coated cells promote immune tolerance, preventing autoimmunity and offering new therapeutic targets.
Area of Science:
- Immunology
- Molecular Biology
- Autoimmunity
Background:
- Complete genetic deficiency of complement protein C1q is strongly associated with Systemic Lupus Erythematosus (SLE) in humans.
- C1q aids phagocytes in clearing apoptotic cells (ACs), preventing the release of inflammatory damage-associated molecular patterns (DAMPs).
- Previous studies indicated C1q-opsonized apoptotic cells promote anti-inflammatory cytokine production by macrophages (Mϕ) and dendritic cells (DCs).
Purpose of the Study:
- To elucidate the molecular mechanisms linking C1q deficiency to SLE pathogenesis.
- To investigate the immunomodulatory effects of C1q-opsonized apoptotic cells on Mϕ and DCs.
- To determine how C1q-mediated phagocytosis influences T cell responses and adaptive immunity.
Main Methods:
- Analysis of surface marker expression (PD-L1, PD-L2, CD40, CD86) on Mϕ and DCs after ingesting C1q-bound apoptotic cells (C1q-polarized cells).
- Mixed Lymphocyte Reaction (MLR) assays to assess the impact of C1q-polarized Mϕ and DCs on T helper (Th) and regulatory T (Treg) cell proliferation.
- Comparison of immune responses induced by C1q-polarized cells versus cells opsonized without C1q.
Main Results:
- C1q-polarized Mϕ exhibited elevated PD-L1/PD-L2 and suppressed CD40; C1q-polarized DCs showed higher PD-L2 and reduced CD86.
- C1q-polarized Mϕ significantly suppressed Th17 and Th1 proliferation and tended to increase Treg proliferation in MLR.
- C1q-polarized DCs decreased autologous Th17 and Th1 proliferation compared to DCs ingesting apoptotic cells without C1q.
Conclusions:
- C1q-opsonized apoptotic cells induce Mϕ and DCs that regulate T effector cell activation, promoting immune tolerance.
- This C1q-dependent immunomodulation helps prevent autoimmunity by 'sculpting' the adaptive immune response.
- The identified pathways involving C1q-polarized Mϕ and DCs represent novel therapeutic targets for SLE and other autoimmune diseases.
Abstract:
A complete genetic deficiency of the complement protein C1q results in SLE with nearly 100% penetrance in humans, but the molecular mechanisms responsible for this association have not yet been fully determined. C1q opsonizes ACs for enhanced ingestion by phagocytes, such as Mϕ and iDCs, avoiding the extracellular release of inflammatory DAMPs upon loss of the membrane integrity of the dying cell. We previously showed that human monocyte-derived Mϕ and DCs ingesting autologous, C1q-bound LALs (C1q-polarized Mϕ and C1q-polarized DCs), enhance the production of anti-inflammatory cytokines, and reduce proinflammatory cytokines relative to Mϕ or DC ingesting LAL alone. Here, we show that C1q-polarized Mϕ have elevated PD-L1 and PD-L2 and suppressed surface CD40, and C1q-polarized DCs have higher surface PD-L2 and less CD86 relative to Mϕ or DC ingesting LAL alone, respectively. In an MLR, C1q-polarized Mϕ reduced allogeneic and autologous Th17 and Th1 subset proliferation and demonstrated a trend toward increased Treg proliferation relative to Mϕ ingesting LAL alone. Moreover, relative to DC ingesting AC in the absence of C1q, C1q-polarized DCs decreased autologous Th17 and Th1 proliferation. These data demonstrate that a functional consequence of C1q-polarized Mϕ and DC is the regulation of Teff activation, thereby "sculpting" the adaptive immune system to avoid autoimmunity, while clearing dying cells. It is noteworthy that these studies identify novel target pathways for therapeutic intervention in SLE and other autoimmune diseases.
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