Notch2 deficiency generates functionally impaired cDCs and macrophages that correlates with intestinal dysbiosis and low-grade inflammation

Authors

• G Cvijetic
• M Mitrovic
• P Fernandes Rodrigues
• IO Conway
• E Reinoso Jacome
• B Mendoza-Bonilla
• J Shi
• A Du Halgouet
• V Ottaviani
• R Tussiwand

Abstract

Myeloid cells including conventional dendritic cells (cDCs) and macrophages are key responders at epithelial barriers, regulating immunity to microbial pathogens and commensals. Equipped with innate receptors, DCs and macrophages sample and monitor the environment, maintaining homeostasis. Upon detection of danger signals they become activated, secrete inflammatory cytokines, and promote T cell activation. Myeloid cells at barrier tissues may therefore be critical players controlling the balance between tolerance and immunity. Within CD11c expressing cells, Notch2 deficiency impairs type 2 dendritic cells (cDC2), resulting in increased susceptibility to C. rodentium as previously shown. In these mice we observed defects also within several macrophage subsets. Besides the reported TH17 defect, linked to the lack of ESAM+cDC2, dysfunctional macrophages may also be involved in the observed compromised barrier function. The lack of Notch2 within the myeloid compartment was accompanied by intestinal dysbiosis and low-grade inflammation. The microbial imbalance and increased CFUs could be transferred by co-housing. The dysbiosis led to increased susceptibility to DSS-induced colitis in Notch2 deficient mice. These results suggest that expression of Notch2 in either one or more myeloid subsets are responsible for the maintenance of a healthy commensal community or that they control immunity to specific opportunistic pathogens. Among the dysregulated pathways, we have focused our attention on innate immune mechanisms and identified several candidate genes that may play a fundamental role in regulating bacterial growth. Collectively, we hypothesize that Notch2 deficiency alters the functional properties of intestinal cDCs and macrophages, ultimately leading to dysbiosis and low-grade inflammation.

Scientific Focus Area: Immunology

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