bims-nocaut Biomed News
on Non-canonical autophagy
Issue of 2024–11–03
two papers selected by
Quentin Frenger, University of Strasbourg
  1. Efferocytosis dysfunction in CXCL4-induced M4 macrophages: phenotypic insights in systemic sclerosis in vitro and in vivo.
  2. Toll-like receptor 7 protects against intestinal inflammation and restricts the development of colonic tissue-resident memory CD8+ T cells.
  1. Front Immunol. 2024 ;15 1468821
    Efferocytosis dysfunction in CXCL4-induced M4 macrophages: phenotypic insights in systemic sclerosis in vitro and in vivo.
    Erwan Le Tallec, Nessrine Bellamri, Marie Lelong, Claudie Morzadec, Quentin Frenger, Alice Ballerie, Claire Cazalets, Alain Lescoat, Frédéric Gros, Valérie Lecureur.
       Introduction: Systemic sclerosis (SSc) is an autoimmune disease characterized by antinuclear antibody production, which has been linked to an excess of apoptotic cells, normally eliminated by macrophages through efferocytosis. Additionally, circulating levels of CXCL4, a novel SSc biomarker, correlate with more severe fibrotic manifestations of the disease. Considering the defective efferocytosis of macrophages in SSc and the CXCL4-related M4 macrophage phenotype, we hypothesized that CXCL4 could be involved in the alteration of phagocytic functions of macrophages in SSc, including LC3-associated phagocytosis (LAP), another phagocytic process requiring autophagy proteins and contributing to immune silencing.
    Methods: In this study, CXCL4 levels were measured by ELISA in vitro in the serum of SSc patients, and also in vivo in the serum and lungs of C57BL/6J SSc mice induced by intradermal injections of hypochloric acid (HOCl) or Bleomycin (BLM), with evaluation of M4 markers. Circulating monocytes from healthy donors were also differentiated in vitro into M4 monocytes-derived macrophages (MDMs) in the presence of recombinant CXCL4. In M4-MDMs, phagocytosis of fluorescent beads and expression level of efferocytic receptors were evaluated by flow cytometry in vitro, while efferocytosis of pHrodo-stained apoptotic Jurkat cells was evaluated by real-time fluorescence microscopy. LAP quantification was made by fluorescence microscopy in M4-MDMs exposed to IgG-coated beads as well as apoptotic Jurkat cells.
    Results: Our results demonstrated that efferocytosis was significantly reduced in M0-MDMs from healthy donors exposed to the CXCL4-rich plasma of SSc patients. In vivo, CXCL4 expression was increased in the lungs of both SSc-mouse models, along with elevated M4 markers, while efferocytosis of BLM-mice alveolar macrophages was decreased. In vitro, M4-MDMs exhibited reduced efferocytosis compared to M0-MDMs, notably attributable to lower CD36 receptor expression and impaired phagocytosis capacities, despite enhanced LAP. Autophagic gene expression was increased both in vitro in SSc MDMs and in vivo in BLM mice, thus acting as a potential compensatory mechanism.
    Discussion: Altogether, our results support the role of CXCL4 on the impaired efferocytosis capacities of human macrophages from SSc patients and in SSc mice.
    Keywords:  CXCL4; efferocytosis; fibrosis; macrophage; phagocytosis; systemic sclerosis
    DOI:  https://doi.org/10.3389/fimmu.2024.1468821
  2. Front Immunol. 2024 ;15 1465175
    Toll-like receptor 7 protects against intestinal inflammation and restricts the development of colonic tissue-resident memory CD8+ T cells.
    Hussein Hamade, Masato Tsuda, Naoki Oshima, Dalton T Stamps, Michelle H Wong, Jasmine T Stamps, Lisa S Thomas, Brenda C Salumbides, Caroline Jin, Jordan S Nunnelee, Deepti Dhall, Stephan R Targan, Kathrin S Michelsen.
       Introduction: The maintenance of intestinal homeostasis depends on a complex interaction between the immune system, intestinal epithelial barrier, and microbiota. Alteration in one of these components could lead to the development of inflammatory bowel diseases (IBD). Variants within the autophagy gene ATG16L1 have been implicated in susceptibility and severity of Crohn's disease (CD). Individuals carrying the risk ATG16L1 T300A variant have higher caspase 3-dependent degradation of ATG16L1 resulting in impaired autophagy and increased cellular stress. ATG16L1-deficiency induces enhanced IL-1β secretion in dendritic cells in response to bacterial infection. Infection of ATG16L1-deficient mice with a persistent strain of murine norovirus renders these mice highly susceptible to dextran sulfate sodium colitis. Moreover, persistent norovirus infection leads to intestinal virus specific CD8+ T cells responses. Both Toll-like receptor 7 (TLR7), which recognizes single-stranded RNA viruses, and ATG16L1, which facilitates the delivery of viral nucleic acids to the autolysosome endosome, are required for anti-viral immune responses.
    Results and discussion: However, the role of the enteric virome in IBD is still poorly understood. Here, we investigate the role of TLR7 and ATG16L1 in intestinal homeostasis and inflammation. At steady state, Tlr7-/- mice have a significant increase in large intestinal lamina propria (LP) granzyme B+ tissue-resident memory CD8+ T (TRM) cells compared to WT mice, reminiscent of persistent norovirus infection. Deletion of Atg16l1 in myeloid (Atg16l1ΔLyz2 ) or dendritic cells (Atg16l1ΔCd11c ) leads to a similar increase of LP TRM. Furthermore, Tlr7-/- and Atg16l1ΔCd11c mice were more susceptible to dextran sulfate sodium colitis with an increase in disease activity index, histoscore, and increased secretion of IFN-γ and TNF-α. Treatment of Atg16l1ΔCd11c mice with the TLR7 agonist Imiquimod attenuated colonic inflammation in these mice. Our data demonstrate that ATG16L1-deficiency in myeloid and dendritic cells leads to an increase in LP TRM and consequently to increased susceptibility to colitis by impairing the recognition of enteric viruses by TLR7.
    Conclusion: In conclusion, the convergence of ATG16L1 and TLR7 signaling pathways plays an important role in the immune response to intestinal viruses. Our data suggest that activation of the TLR7 signaling pathway could be an attractive therapeutic target for CD patients with ATG16L1 risk variants.
    Keywords:  ATG16L1; CD8+ Trm; TLR7; autophagy; inflammatory bowel diseases; plasmacytoid dendritic cells
    DOI:  https://doi.org/10.3389/fimmu.2024.1465175
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