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Chronic inflammation driven by IFN-g leads to global disruption of monocyte/macrophage homeostasis

Thursday, September 13, 2018 — Poster Session III

12:00 p.m. – 1:30 p.m.
FAES Terrace
NCI
IMMUNO-19

Authors

  • L Magalhaes
  • Q Chen
  • A Huang
  • K Lam
  • R Araya
  • G Altan-Bonnet
  • R Goldszmid

Abstract

Monocytes and macrophages are critical in host defense and tissue repair. In mice Ly6Chi, classical monocytes give rise to Ly6Clow patrolling monocytes, however, the signals that regulate this differentiation remain unknown. Ly6Chi monocytes are recruited to sites of infection and differentiate into inflammatory macrophages. The contribution of these cells needs to be transient followed by restoration of tissue homeostasis. We hypothesized that the immune adaptation needed to cope with a chronic infection has deleterious effects on monocyte/macrophage homeostasis. To address this, we used a model of chronic T. gondii infection. Chronic infection results in the loss of Ly6Clow monocytes in blood and bone marrow (BM), and the loss of resident macrophages in several tissues (e.g. lung, peritoneum, brain), which are replaced by monocyte-derived cells. Importantly, chronically infected mice showed impaired response to a secondary microbial challenge. To determine if this phenomenon was driven by chronic exposure to IFN-g, we performed loss/gain of function experiments and revealed that IFN-g is necessary and sufficient to drive the disappearance of resident macrophages and Ly6Clow monocytes. Furthermore, we observed a similar loss of Ly6Clow monocytes in a systemic lupus erythematosus model characterized by sustained levels of IFN-g. Mechanistically, IFN-g inhibited the upregulation of CSF1 receptor, a critical differentiation and survival factor for Ly6Clow monocytes and resident macrophages. Our findings reveal a previously unappreciated role for IFN-g in controlling the differentiation of monocyte subsets and indicate that chronic exposure to IFN-g reshapes the innate immune landscape of the host.

Category: Immunology