The Class A Macrophage Scavenger Receptor Is a Major Pattern Recognition Receptor for Neisseria meningitidis Which Is Independent of Lipopolysaccharide and Not Required for Secretory Responses

Macrophages (Mφ) play a key role in the pathogenesis of invasive meningococcal infections. The roles of two pattern recognition molecules, the Mφ scavenger receptor (SR-A) and Toll-like receptor 4 (TLR-4), have been investigated using bone marrow culture-derived Mφ (BMMφ). Surprisingly, a comparison of BMMφ from wild-type and SR-A knockout (SR-A(−/−)) mice showed that nonopsonic phagocytosis of meningococci was mediated almost exclusively via SR-A. Previous studies have demonstrated only a partial involvement of the receptor in the uptake of other bacteria, such as Escherichia coli. Interestingly, we also show that lipopolysaccharide (LPS) was not the ligand for the receptor on these organisms. Further study of the downstream events of SR-A-mediated ingestion of Neisseria meningitidis demonstrated that SR-A was not required for cytokine production. To determine the bacterial and host factors required to stimulate Mφ activation, we examined TLR-4-deficient Mφ from C3H/HeJ mice and LPS-deficient meningococci. TLR-4-deficient cells elaborated reduced amounts of tumor necrosis factor alpha, interleukin-12 (IL-12), and IL-10, even though ingestion via SR-A was unaffected in these cells. Similarly, although there was no change in SR-A-mediated ingestion of LPS-deficient meningococci, the mutant failed to stimulate a Mφ-dependent cytokine response. Thus, we show that Mφ SR-A mediates opsonin-independent uptake of N. meningitidis independently of lipid A and that this activity is uncoupled from the Mφ secretion of proinflammatory cytokines, which provides a basis for further investigation of the role of this receptor in meningococcal disease in humans.