Abstract
Impaired clearance of dying and dead cells by professional and amateur phagocytes plays a crucial role in the etiology of systemic lupus erythematosus (SLE). While dying, cells expose and release a plethora of eat-me and find-me signals to ensure their timely removal before entering the dangerous stage of secondary necrosis. A well-described chemoattractant for macrophages is dying cell-derived lysophosphatidylcholine (LPC). However, its implications for and/or its association with SLE disease, so far, have not been examined. In the present study, we analyzed the LPC serum concentrations of patients with SLE and rheumatoid arthritis (RA). Subsequently, we examined if and to which extent the measured serum concentrations of LPC and an LPC-rich environment can impact the phagocytosis of necrotic cells. Sera from patients with SLE, RA, and normal healthy donors (NHD) were characterized for several parameters, including LPC concentrations. Phagocytosis of dead cells by human macrophages in the presence of SLE and NHD sera was quantified. Additionally, the impact of exogenously added, purified LPC on phagocytosis was analyzed. Patients with SLE had significantly increased LPC serum levels, and high serum LPC of SLE patients correlated significantly with impaired phagocytosis of dead cells in the presence of heat-inactivated serum. Phagocytosis in the presence of sera from NHD showed no correlation to LPC levels, but exogenous addition of purified LPC in the range as measured in SLE patients' sera led to a concentration-dependent decrease. Our data show that high levels of LPC as observed in the sera of SLE patients have a negative impact on the clearance of dead cells by macrophages. Chemoattraction requires a concentration gradient. The higher the LPC concentration surrounding a dying or dead cell, the smaller the achievable gradient upon LPC release will be. Thus, it is feasible to assume that elevated LPC levels can interfere with the build-up of a local LPC gradient during cell death, and hence might play a role in the establishment and/or perpetuation of SLE disease.
Highlights
The process of apoptotic cell clearance—commonly referred to as efferocytosis—works with an impressively high degree of effectiveness and eliminates billions of dying cells in the context of tissue homeostasis and cell turnover every day [1]
We focused on LPC and analyzed the corresponding serum levels in systemic lupus erythematosus (SLE) patients, patients with rheumatoid arthritis (RA), and normal healthy donors (NHD)
We observed significantly increased LPC serum levels in the SLE group and high levels in patients with involvement of vessels or kidneys, respectively
Summary
The process of apoptotic cell clearance—commonly referred to as efferocytosis—works with an impressively high degree of effectiveness and eliminates billions of dying cells in the context of tissue homeostasis and cell turnover every day [1]. The co-existence of ANAs and accumulated SNEC leads to the formation of immune complexes in several tissues [9]. This favors a pathological, proinflammatory mode of elimination leading to increased organ damage and accumulation of more dying cell debris, fueling a self-amplifying vicious circle [10]. The result is a systemic type I interferon signature in response to the ANA–SNEC complexes analogous to a viral infection [3, 11]
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