Apoptosis is fundamental to the development and maintenance of animal tissues and the immune system. Rapid clearance of apoptotic cells by macrophages is important to inhibit inflammation and autoimmune responses against intracellular antigens. Here we report a new function for Mer, a member of the Axl/Mer/Tyro3 receptor tyrosine kinase family. mer(kd) mice with a cytoplasmic truncation of Mer had macrophages deficient in the clearance of apoptotic thymocytes. This was corrected in chimaeric mice reconstituted with bone marrow from wild-type animals. Primary macrophages isolated from mer(kd) mice showed that the phagocytic deficiency was restricted to apoptotic cells and was independent of Fc receptor-mediated phagocytosis or ingestion of other particles. The inability to clear apoptotic cells adequately may be linked to an increased number of nuclear autoantibodies in mer(kd) mice. Thus, the Mer receptor tyrosine kinase seems to be critical for the engulfment and efficient clearance of apoptotic cells. This has implications for inflammation and autoimmune diseases such as systemic lupus erythematosus.

Mice lacking the membrane tyrosine kinase c-mer have been shown to have altered macro-phage cytokine production and defective phagocytosis of apoptotic cells despite normal phagocytosis of other particles. We show here that c-mer–deficient mice have impaired clearance of infused apoptotic cells and that they develop progressive lupus-like autoimmunity, with antibodies to chromatin, DNA, and IgG. The autoimmunity appears to be driven by endogenous antigens, with little polyclonal B cell activation. These mice should be an excellent model for studying the role of apoptotic debris as an immunogenic stimulus for systemic autoimmunity.

Mer tyrosine kinase (MerTK) is a major macrophage apoptotic cell (AC) receptor. Its functional impairment promotes autoimmunity and atherosclerosis, while overexpression correlates with poor prognosis in cancer. However, little is known about mechanisms regulating MerTK expression in humans. We found that MerTK expression is heterogenous among macrophage subsets, being mostly restricted to anti-inflammatory “M2c” (CD14+CD16+CD163+CD204+CD206+CD209−) cells, differentiated by M-CSF or glucocorticoids. Small numbers of MerTK+ “M2c-like” cells are also detectable among circulating CD14brightCD16+ monocytes. MerTK expression levels adapt to changing immunological environment, being suppressed in M1 and “M2a” macrophages, and in dendritic cells. Remarkably, while glucocorticoid-induced differentiation is IL-10-independent, M-CSF-driven M2c polarization and related MerTK up-regulation require IL-10. However, neither IL-10 alone nor TGFβ are sufficient to fully differentiate M2c (CD16+CD163+MerTK+) macrophages. M-CSF and IL-10, both released by T lymphocytes, may thus be required together to promote regulatory T cell-mediated induction of anti-inflammatory monocytes-macrophages. MerTK enables M2c macrophages to clear early ACs more efficiently than other macrophage subsets, and mediates AC clearance by CD14brightCD16+ monocytes. Moreover, M2c cells release Gas6, which in turn amplifies IL-10 secretion via MerTK. IL-10-dependent induction of the Gas6/MerTK pathway may, therefore, constitute a positive loop for M2c macrophage homeostasis and a critical checkpoint for maintenance of anti-inflammatory conditions. Our findings give new insight into human macrophage polarization and favor a central role for MerTK in regulation of macrophage functions. Eliciting M2c polarization can have therapeutic utility for diseases such as lupus, in which a defective AC clearance contributes to initiate and perpetuate the pathological process.

The autosomal recessive lpr and gld genes induce in mice multiple autoantibodies and the progressive accumulation of large numbers of non-malignant CD4- CD8- T lymphocytes. The clinical syndromes and immune abnormalities associated with these two nonallelic genes are nearly identical and are also highly dependent on background genes. MRL/lpr mice are particularly severely affected, and they develop a syndrome that is serologically and pathologically similar to human systemic lupus erythematosus (SLE). Abnormal cell marker expression in the aberrant lpr T lymphocytes includes surface antigens normally associated with activated T cells or even with B cells, and it occurs along with enhanced expression of certain oncogenes. The lpr gene results in intrinsic abnormalities of both T and B lymphocytes, yet its location and product are unknown. The gld gene is located on chromosome 1; its product is also unknown. Although many immunological abnormalities are known, the mechanism whereby these two genes induce autoimmunity and lymphoproliferation remains obscure. Further studies of mice bearing these mutant genes are certain to yield insights into systemic autoimmunity and the control of lymphocyte proliferation.

We examined the prevalence of clinical and immunologic features of systemic lupus erythematosus (SLE) by race, sex and age in a population-based study of 265 SLE patients. Patients fulfilled the American College of Rheumatology classification criteria. The median time between diagnosis and study enrollment was 13 months. The clinical and hematologic data were limited to occurrences up to 6 months after the diagnosis date, as documented in medical records. We used sera collected at study enrollment from 244 (92%) patients for serologic testing of autoantibodies. The associations between clinical and immunological features of SLE and age, sex and race were examined using logistic regression. The effect of each of these variables was examined adjusting for the other two demographic factors. Mean age at diagnosis was 6 years younger among African-Americans and other minorities compared with white patients (P < 0.01). Discoid lupus, proteinuria, anti-Sm and anti-RNP autoantibodies were more commonly seen in African-American patients, with odds ratios higher than 3.0. Photosensitivity and mucosal ulcers were noted less often in African-American patients. Proteinuria, leukopenia, lymphopenia and thrombocytopenia were approximately three times more common in men compared with women. The prevalence of oral or nasal ulcers and anti-DNA autoantibodies declined with age. The extent to which the differences we observed reflect genetic or environmental influences on the disease process should be investigated.