PTEN inhibits scavenger receptor–mediated phagocytosis of methicillin-resistant <i>Staphylococcus aureus</i>

Phagocytosis requires the coordination of various classes of receptors and the activation of multiple signaling programs, culminating in actin cytoskeletal rearrangement and ingestion. Given the pleiotropic nature of the events necessary for proper microbial ingestion, identifying molecules that control distinct steps of phagocytosis could reveal potential strategies to enhance microbial clearance. PTEN is a lipid/protein phosphatase traditionally recognized as a tumor suppressor. While PTEN inhibits various arms of the innate immune response, its role during Staphylococcus aureus infection remains unclear. We hypothesize that PTEN inhibits the functions of scavenger receptors (SRs) and the actin cytoskeleton during methicillin-resistant S. aureus (MRSA) infection in macrophages. RNAseq analysis of PTEN KO immortalized bone marrow-derived macrophages (iBMDMs) unveiled increased expression of genes involved in actin polymerization, pathogen recognition, and SRs, which leads to enhanced MRSA phagocytosis in both iBMDMs and primary peritoneal macrophages lacking PTEN. PTEN is physically associated with 2 SRs, MARCO and CD36, and blocking these receptors prevents the increased phagocytosis seen in PTEN KO macrophages. PTEN binds to the actin depolymerizing factor cofilin-1 during infection, inhibiting F-actin (the essential form of actin for phagocytosis) while increasing G-actin pools. Cytometry by time of flight (CyTOF) analysis of human myeloid cell populations from a PTEN-haploinsufficient patient suggests that PTEN is necessary for generating specific monocyte and dendritic subclasses. This study identifies the role of PTEN in macrophage phagocytosis of a gram-positive pathogen and in the development of monocyte subsets. This highlights the spectrum of PTEN importance in host defense mechanisms in both murine and human phagocytes.