Macrophage phosphatidylserine recognition pathway

The macrophage phosphatidylserine (PS) recognition pathway is a critical biological axis responsible for the identification and clearance of apoptotic cells, a process termed efferocytosis (Elliott & Ravichandran, 2010, Nature). In healthy cells, PS is sequestered in the inner leaflet of the plasma membrane, but it flips to the outer leaflet during apoptosis, acting as a universal eat-me signal (Birge et al., 2016, Cell Death & Differentiation). Macrophages recognize externalized PS through a variety of receptors, including the TIM family (TIM-1, TIM-4) and the TAM family (Tyro3, Axl, MerTK), often facilitated by bridging proteins like Gas6 and Protein S (Lemke, 2013, Nature Reviews Immunology). In the tumor microenvironment, PS is frequently overexposed on both tumor cells and tumor-associated vessels, where it acts as an immune checkpoint by promoting an anti-inflammatory, M2-like macrophage phenotype that suppresses T-cell activity (Huang et al., 2011, Cancer Research). Therapeutic strategies targeting this pathway include monoclonal antibodies that bind PS (e.g., Bavituximab) and small molecule inhibitors of TAM receptors (e.g., Sitravatinib, Bemcentinib) to reverse immunosuppression and enhance anti-tumor responses. Dysregulation of this pathway is also a hallmark of autoimmune diseases like systemic lupus erythematosus (SLE), where defective clearance of apoptotic debris leads to the loss of self-tolerance (Munoz et al., 2010, Nature Reviews Rheumatology).

Other names

Efferocytosis pathwayPhosphatidylserine signaling axisPS-mediated phagocytosisApoptotic cell clearance pathway

Blockade of phosphatidylserine-mediated immunosuppression and modulation of macrophage-mediated efferocytosis to enhance anti-tumor immunity or resolve chronic inflammation.