Response of peritoneal macrophages to infection and tumor metastasis

Resumen

The peritoneal cavity is exposed to life-threatening infections and neoplastic aggressions, but the immune defense mechanisms involved in the control of peritoneal infections and metastatic tumor development are largely unknown. In this thesis, we describe that peritoneal tissue-resident macrophages (LPMs) carry out a direct defense function efficiently clearing bacteria during peritoneal E. coli infection. Internalization and elimination of bacteria by LPMs is associated with the formation of specialized multicellular structures attached to the peritoneal mesothelium, that we termed resMØ-aggregates. ResMØ-aggregates are transient and dynamic structures, crucial for an effective control of infection that provide a physical support and microenvironment, allowing the interaction and function of peritoneal immune cells, free in the peritoneal fluid in homeostasis. The formation of resMØ-aggregates is dependent on fibrin polymerization, a process controlled by tissue factor derived from by mesothelial cells. In addition to their direct role in the elimination of bacteria, LPMs also participate in the removal of dead cells within resMØ-aggregates and in fibrinolysis, a process leading to resMØ-aggregate disruption during the resolution of infection. The recruitment of monocyte-derived cells to the peritoneal cavity and to resMØ-aggregates further contribute to the fibrinolysis process, and to dampening inflammation during the resolution of infection. Similar structures, essentially composed of tumor cells and LPMs, are formed during the development of peritoneal colorectal tumor metastases, a process that is immunologically silent, in contrast to peritoneal E. coli infection, that causes a strong inflammatory reaction. During E. coli infection, LPMs rapidly migrate to the omentum and control leukocyte recruitment to milky spots, a process that might be required for the induction of additional defense mechanisms. The formation of structures similar to resMØ-aggregates may also occur during infection or metastasis development in other body cavities, such as the pleural cavity or the brain ventricular system, harboring macrophages in a fluidic environment, that may need to attach to the epithelium lining of these cavities to fulfill their immune defense functions.