Mouse Tissue-Resident Peritoneal Macrophages in Homeostasis, Repair, Infection, and Tumor Metastasis

Abstract

Large peritoneal macrophages (LPMs) are long-lived, tissue-resident macrophages, formed during embryonic life, developmentally and functionally confined to the peritoneal cavity. LPMs provide the first line of defense against life-threatening pathologies of the peritoneal cavity, such as abdominal sepsis, peritoneal metastatic tumor growth, or peritoneal injuries caused by trauma, or abdominal surgery. Apart from their primary phagocytic function, reminiscent of primitive defense mechanisms sustained by coelomocytes in the coelomic cavity of invertebrates, LPMs fulfill an essential homeostatic function by achieving an efficient clearance of apoptotic, that is crucial for the maintenance of self-tolerance. Research performed over the last few years, in mice, has unveiled the mechanisms by which LPMs fulfill a crucial role in repairing peritoneal injuries and controlling microbial and parasitic infections, reflecting that the GATA6-driven LPM transcriptional program can be modulated by extracellular signals associated with pathological conditions. In contrast, recent experimental evidence supports that peritoneal tumors can subvert LPM metabolism and function, leading to the acquisition of a tumor-promoting potential. The remarkable functional plasticity of LPMs can be nevertheless exploited to revert tumor-induced LPM protumor potential, providing the basis for the development of novel immunotherapeutic approaches against peritoneal tumor metastasis based on macrophage reprogramming.

Keywords: macrophages; monocyte-derived macrophages; peritoneal cavity; peritoneal injury; peritoneal metastasis; peritoneal sepsis; tissue-resident macrophages.

Figure 1

Schematic representation of cell surface receptors expressed by embryonic LPMs. The LPM transcriptional program driven by CFS1 and retinoic acid, through the transcription factors PU.1 and GATA6, controls the expression of cell surface molecules characteristic of embryonic LPMs, such as markers of tissue‐resident macrophages, adhesion molecules, and receptors involved in recognition of dead cells, pathogen binding, pathogen‐induced activation, and negative‐regulation of LPM activation. Of note, only the most representative cell surface molecules expressed by embryonic LPMs have been included in this figure.

Figure 2

Integrated model of the origin and replacement of LPMs in steady state and inflammation. LPMs differentiate during embryonic life and maintain themselves by in situ self‐renewal during adult life. Resident embryonic LPMs were claimed to derive either from a dual contribution from yolk sac macrophages and fetal liver monocytes, or exclusively from fetal liver monocytes. Embryonic LPMs are gradually, yet partially, replaced from the late stages of embryonic development by resident moLPMs, that acquire a resident embryonic LPM identity, but retained some transcriptional and functional characteristics related to their origin. Changes in the peritoneal microenvironment, that arise upon sexual maturity, leads to a sexually dimorphic replacement of embryonic LPMs by resident moLPMs, the replacement rate being higher in males than in females. Inflammatory reactions in the peritoneal cavity can lead to resident LPM cell death leading to a reduction in the number of resident LPMs, whose extent correlates with the severity of inflammation. Recovery of the original LPM pool occurs by proliferation of the remaining resident LPMs and replacement by ii‐moLPMs. ii‐moLPMs formed after mild inflammation co‐exist long‐term with remaining resident LPMs, but do not acquire a resident LPM phenotype, due to competition with resident LPMs and alterations in peritoneal environment. In contrast, severe inflammation can lead to the total ablation of resident LPMs, which are ultimately replaced by ii‐moLPMs, that acquire a resident LPM identity, but maintained transcriptionally and functionally divergent features, determined by their origin, peritoneal inflammation, and time‐of‐residency.

Figure 3

Recent experimental advances revealing the formation of mesothelium‐bound LPM aggregates induced by peritoneal injury or bacterial infection. 1) Formation of thrombus‐like structures in response to focal mesothelial injury. Imaging of the peritoneal cavity after laser‐induced focal thermal peritoneal injury, by intravital microscopy through the intact abdominal wall, revealed that LPMs attached to the damaged peritoneum, forming thrombus‐like structures dependent on scavenger receptors containing SRCR domains, that contribute to the repair of peritoneal lesions.^{[ 4 ]} A) Schematic representation of a thrombus‐like structure formed by LPM aggregates at 30 min after induction of injury. B) Enlargement of the area marked in (A). 1: LPMs; 2: mesothelial cells; 3: activated mesothelial cells; 4: apoptotic mesothelial cells. Reproduced with permission.^{[ 4 ]} Copyright 2021, AAAS. 2) Formation of adhesions in response of severe peritoneal injury. Using an experimental model of peritoneal adhesion formation induced by surgical sterile injury, high numbers of LPMs were reported to form extensive aggregates that promoted the deposition of fibrin and the growth of scar tissue, leading to the formation of peritoneal adhesions within 7 days after surgery.^{[ 4} , ^{59 ]} C) Schematic representation of the induction of a peritoneal adhesion by extensive aggregation of LPMs over the injured tissue, forming a bridge between opposing peritoneal surfaces. D) Enlargement of the area marked in (C). 1: LPMs; 2: activated mesothelial cells; 3: fibrin. Reproduced with permission.^{[ 4 ]} Copyright 2021, AAAS. 3) Formation of resMØ‐aggregates in response to E. coli infection. Using a mouse model of sublethal sepsis, LPMs were recently demonstrated to promote the formation of mesothelium‐bound, fibrin‐dependent, resMØ‐aggregates, composed by sequentially‐recruited LPMs, B1‐cells, neutrophils, and moCs, that provided a physical scaffold allowing the interaction and function of peritoneal immune cells. During the resolution of infection, LPMs controlled the recruitment of moCs to resMØ‐aggregates, that were essential for fibrinolysis‐mediated resMØ‐aggregate disaggregation, leading to dampening of inflammation.^{[ 47 ]} E) Schematic representation of the formation of a resMØ‐aggregate at 90 min after infection. F) Enlargement of the area marked in (E). G) Schematic representation of the disruption a resMØ‐aggregate at 24 h after infection. H) Enlargement of the area marked in G). 1: LPMs; 2: LPMs containing bacteria; 3: necrotic LPMs containing bacteria; 4: LPMs containing dead cells and fibrin; 5: moCs; 6: moCs containing dead cells and fibrin; 7: B cells; 8: neutrophils; 9: neutrophils containing bacteria; 10: neutrophils containing dead cells; 11: activated mesothelial cells; 12: bacteria; 13: fibrin. Reproduced with permission.^{[ 47 ]} Copyright 2021, Elsevier.