Transcriptional control of mononuclear phagocytes in homeostasis and disease

Bart N. Lambrecht, VIB Center for Inflammation Research, Ghent, Belgium

IRF4 and IRF8 are key transcription factors controlling monocyte and DC development and function.  In this talk, I will give 2 examples on how these TFs can control key aspects of macrophage homeostasis and disease.

Mice deficient in IRF8 fail to develop cDC1 and monocytes and have a myeloproliferative syndrome. By disentangling the effects of IRF8 deficiency, we report that the well-known accumulation of neutrophils in Irf8-/- mice requires two independent hits; IRF8 must be simultaneously absent from myeloid progenitors as well as from mature macrophages. Whereas loss of IRF8 promotes the generation of neutrophils from progenitors, macrophage-specific loss of IRF8 and its downstream target FLT3 impaired their trans surveillance ability to consume FLT3L, the growth factor driving neutrophil accumulation. As neutrophils and macrophages represent alternative fates downstream of granulocyte-macrophage progenitors, we propose that cell fate decisions are accompanied by the institution of “counting” mechanisms, in the form of growth factor regulation by cells of opposing fates to maintain stable cell ratios across the organism. 

Tissue resident alveolar macrophages (trAMs) are generally considered as resilient immunoregulatory cells that safeguard the alveolar space from overzealous inflammation that would compromise gas exchange.  Using mice in which trAMs can be specifically deleted and replaced, we show that trAMs can also act as pro-inflammatory cells that orchestrate type-2 immunity in the lungs. After house dust mite allergen inhalation, the alarmin IL-33 primes ILC2s to produce IL-13 which reprograms trAMs by upregulation of IRF4. While trAM identity is rapidly lost due to chromatin remodeling and downregulation of PPARg dependent homeostatic genes, IRF4-dependent binding and transcription at loci coding for chemokines and cell-cell fusion machinery leads to recruitment of granulocytes, ILC2s and Tregs to the alveolar space, and to formation of multinucleated giant cells. Therefore, trAMs are highly versatile cells that tightly control recruitment of inflammatory cells to the alveolar space and can be reprogrammed to drive lung inflammation via IRF4.