Axl receptor induces efferocytosis, dampens M1 macrophage responses and promotes heart pathology in Trypanosoma cruzi infection

Abstract

Adaptive immunity controls Trypanosoma cruzi infection, but the protozoan parasite persists and causes Chagas disease. T cells undergo apoptosis, and the efferocytosis of apoptotic cells might suppress macrophages and exacerbate parasite infection. Nonetheless, the receptors involved in the efferocytosis of apoptotic lymphocytes during infection remain unknow. Macrophages phagocytose apoptotic cells by using the TAM (Tyro3, Axl, Mer) family of receptors. To address how the efferocytosis of apoptotic cells affects macrophage-mediated immunity, we employ here Axl receptor- and Mer receptor-deficient mouse strains. In bone marrow-derived macrophages (BMDMs), both Axl and Mer receptors play a role in the efferocytosis of proapoptotic T cells from T. cruzi-infected mice. Moreover, treatment with a TAM receptor inhibitor blocks efferocytosis and upregulates M1 hallmarks induced by immune T cells from infected mice. Remarkably, the use of Axl−/− but not Mer−/− macrophages increases T-cell-induced M1 responses, such as nitric oxide production and control of parasite infection. Furthermore, infected Axl−/− mice show reduced peak parasitemia, defective efferocytosis, improved M1 responses, and ameliorated cardiac inflammation and fibrosis. Therefore, Axl induces efferocytosis, disrupts M1 responses, and promotes parasite infection and pathology in experimental Chagas disease. Axl stands as a potential host-direct target for switching macrophage phenotypes in infectious diseases.

Differential regulation of lung homeostasis and silicosis by the TAM receptors MerTk and Axl

“…On the other hand, another study found a decrease in M1-associated inflammatory factor production by tumor-associated macrophages in the MDA-MB-231 xenograft breast cancer model ( 38 ). Together, these findings suggest that Axl signaling can trigger or suppress the M1 phenotype in a variety of disease settings ( 39 ). Neutrophils also play an important role in the early stages of respiratory disorders, including silicosis ( 40 ).…”

Immunopathogenesis in Trypanosoma cruzi infection: a role for suppressed macrophages and apoptotic cells

“…To address the role of efferocytosis during T. cruzi infection, we employed two mouse strains individually defective in Axl and Mer, two out of three TAM receptors involved in efferocytosis ( 14 ). Double Mer -/- Axl -/- and single Mer-defective strains have been previously used in Leishmania infection to show that infected neutrophils transfer Leishmania parasites to macrophages or DCs through efferocytosis and reduce macrophage and T cell responses ( 77 , 78 ).…”

“…By employing bone marrow-derived macrophages treated with a TAM receptor inhibitor or Mer- and Axl-defective macrophages, we investigated macrophage responses to T cells from T. cruzi -infected mice, which bear both effector activity and proapoptotic cells ( 14 ). Efferocytosis of apoptotic T cells was blocked by a TAM receptor inhibitor, whereas Mer or Axl deficiency partially inhibited efferocytosis ( 14 ). Remarkably, TAM inhibition and Axl but not Mer deficiency improved M1 responses to T cells from T. cruzi -infected mice ( 14 ).…”

“…Here, we focused on the molecular mechanisms of macrophage activation and deactivation, the dual role of M1 and M2 macrophages in antiparasitic immunity, and their modulation by T cell cytokines and apoptotic cells. We consider classically activated macrophages to be M1, which express IL-12 and induced NO synthase (iNOS), produce NO, and exhibit microbicidal activity ( 14 ). In contrast, alternatively activated M2 macrophages are susceptible to parasite infection ( 15 ), express arginase 1 (Arg1) ( 16 ), and play a role in tissue repair ( 12 ).…”

The Role of TAM Receptors in Bone

“…The role of AXL is controversial with studies showing that induction of M1 macrophage phenotype, but also M2 macrophage signature, can be induced by AXL depending on the cytokine environment and disease context. Additionally, AXL contributes to efferocytosis in the context of inflammatory environments [ 63 , 64 , 65 , 66 ]. In contrast, MERTK is strongly connected to M2 macrophage polarization status and is essential for efferocytosis predominantly in anti-inflammatory environments [ 67 , 68 , 69 , 70 ].…”