Metabolic rewiring tunes dermal macrophages in staphylococcal skin infection

Abstract

The skin needs to balance tolerance of colonizing microflora with rapid detection of potential pathogens. Flexible response mechanisms would seem most suitable to accommodate the dynamic challenges of effective antimicrobial defense and restoration of tissue homeostasis. Here, we dissected macrophage-intrinsic mechanisms and microenvironmental cues that tune macrophage signaling in localized skin infection with the colonizing and opportunistic pathogen Staphylococcus aureus. Early in skin infection, the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by γδ T cells and hypoxic conditions within the dermal microenvironment diverted macrophages away from a homeostatic M-CSF– and hypoxia-inducible factor 1α (HIF-1α)–dependent program. This allowed macrophages to be metabolically rewired for maximal inflammatory activity, which requires expression of Irg1 and generation of itaconate, but not HIF-1α. This multifactorial macrophage rewiring program was required for both the timely clearance of bacteria and for the provision of local immune memory. These findings indicate that immunometabolic conditioning allows dermal macrophages to cycle between antimicrobial activity and protection against secondary infections.

Type I interferon governs immunometabolic checkpoints that coordinate inflammation duringStaphylococcalinfection

“…As infection progresses, the high concentration of host-derived signaling molecules changes the inflammatory context of the MRSA-infected lesion 73–75 . In addition to recruiting peripheral leukocytes, including bactericidal neutrophils, host-derived signaling molecules further refine macrophage programming to allow better orchestration of local immunity 26,39 76–78 . Our data are consistent with a recent study indicating an essential role for IFNAR in macrophage metabolic remodeling during Mycobacterium tuberculosis (Mtb) infection 15 .…”

“…Infection with the bacterial pathogen Staphylococcus aureus elicits a rapid and robust innate immune response’ characterized by enhancement of glycolytic metabolism and itaconate-dependent TCA cycle remodeling 17 35–38 . During S. aureus skin infection, dermal macrophages cycle between a GM-CSF and HIF-1a-driven homeostatic metabolic program and an itaconate-dominated pro-inflammatory metabolic program 39 . These changes in host metabolism facilitate antibacterial immunity, inflammation, immune memory, and inflammation resolution during S. aureus infection.…”

Macrophages recycle phagocytosed bacteria to fuel immunometabolic responses

“…On the other hand, because macrophages rely on the acquisition of extracellular nutrients as all cells in tissue, they are tightly dependent on nutrient availability in the microenvironment. This becomes an issue when metabolites alteration occurs 8,9,56 . Thus, catabolizing engulfed bacteria may also provide a competitive advantage to phagocytes in infected tissues when access to extracellular nutrients is limited or challenged by fast replicating bacteria.…”

“…In the case of macrophages, a cell type specialized in the uptake and removal of dead cells and microorganisms, various nutrients are specifically rerouted upon activation to fulfill energetic demands and to produce signaling metabolites essential to innate immune response specificities 3,[5][6][7] . This makes macrophages particularly sensitive to nutrient availability within tissues, which is often altered at tumor or infection sites [8][9][10][11] . Mammalian cells preferentially metabolize low-molecular-weight nutrients such as glucose and amino acids, which are taken up from the microenvironment through a large variety of plasma membrane transporters 2 .…”

GM-CSF-mediated epithelial-immune cell crosstalk orchestrates pulmonary immunity toAspergillus fumigatus

“…Support for this hypothesis comes from fungal infection models in which lymphocytes produce GM-CSF, exemplified by innate-like lymphocytes during pulmonary Blastomyces dermatitidis infection 15 and NK cells during renal candidiasis. 16 Additionally, during staphylococcal skin infection, γδ T cells make GM-CSF 17 , and in experimental autoimmune encephalomyelitis (EAE), CD4 + T cells are the primary source of GM-CSF in the central nervous system 18 . In the second model, GM-CSF may be derived from the same cell subsets under homeostatic and infectious conditions but require distinct signals for induction.…”