PTEN and the Regulation of Macrophage Antimicrobial Effector Functions

Abstract

Macrophage effector functions include ingestion and killing of microbes, along with induction, maintenance, and chronicity of the inflammatory response. Understanding the host-derived mechanisms that enhance phagocyte antimicrobial effector function is critical for creating treatments to clear the infection. We and others have shown that lipid and protein phosphatase and tensin homolog (PTEN) reduces microbial ingestion and killing during fungal infection in macrophages. In the current work, we found that macrophage PTEN inhibits Methicillin-resistant Staphylococcus aureus (MRSA) phagocytosis in macrophages. PTEN effects are accompanied by reduced gene and protein expression of the scavenger receptors (SRs) MARCO and CD36, hindering receptor-mediated phagocytosis during MRSA infections. We next investigated the killing capacity of macrophages deficient in PTEN and observed enhanced killing compared to control macrophages. To investigate the mechanism of this increase in killing, we measured the pH of these cells and observed increased acidity in the PTEN deficient macrophages. We then investigated the role of PTEN in human phagocytes, using PBMC-derived monocytes from a PTEN haploinsufficient patient and healthy controls. CyTOF analysis showed that certain immune subsets, but not all, were reduced in the patient, highlighting the role for PTEN in the homeostasis of specific monocyte subsets. RNA sequencing analysis gave us further insights into the programming of these cells. Patient monocytes displayed defects in phagosome, lysosome, and innate immune pathways. These results suggest that human and murine PTEN is an important inhibitor of multiple processes during phagocyte effector functions against MRSA infection.