Myeloid Cell Laboratory

Pathophysiology and Therapy of Immune and Inflammatory Diseases
Centro de Investigaciones Biológicas CSIC (CIB)

Macrophages display a huge functional heterogeneity and acquire pro- or anti-inflammatory functions depending on the surrounding tissue microenvironment. The continuum of macrophage polarization/activation states ultimately results from the integration of the plethora ofintracellular signals triggered by the extracellular millieu. The pathophysiological relevance of the balance between polarization states is best exemplified during inflammation. Pro-inflammatory macrophages predominate at the initial stages of an inflammatory response, whereas "tissue-repair"/resolving  macrophages drive resolution of inflammation, and their sequential occurrence is required for the onset and termination of inflammatory responses, and for tissue repair after injury. In consequence, deregulation of the macrophage polarization balance leads to chronic inflammatory pathologies and metabolic disorders (e.g., rheumatoid arthritis, fibrosis, obesity), and its subversion is used by tumors to escape from immune-surveillance and to foster their own proliferation and dissemination. Thus, determination of the mechanisms underlying the differences between polarization states should lead to the identification of molecules which might serve as "predictors" of macrophage function capabilities, or whose manipulation might allow modulating macrophage effector functions under homeostatic or pathological conditions (therapeutic markers).

We have previously defined the transcriptomic profiles of macrophages generated in the presence of either GM-CSF (pro-inflammatory GM-MØ) or M-CSF (anti-inflammatory M-MØ), and identified genes and proteins whose expression is restricted to either macrophage subtype in vitro and marks either pro-inflammatory macrophages (CCR2, activin A, MMP12, EGLN3) or homeostatic tissue-resident macrophages in vivo (HTR2B, CD209, FOLR2, HO1). Besides, we demonstrated that activin A, CCL2 and serotonin (5HT) skew macrophage polarization at the transcriptomic and functional level, that 5HT inhibits pro-inflammatory cytokine production, and that the 5HT receptors HTR2B and HTR7 influence the transcription of functionally relevant genes in macrophages. From these observations, current projects in the lab now address the analysis of the mechanisms by which activin A, MMP12 and 5HT modulate macrophage polarisation through two specific objectives: 1) The determination of the molecular basis for the ability of Activin A, MMP12, and their target genes, to modulate macrophage polarization; and 2) The molecular dissection of the contribution of 5HT, 5HT receptors and 5HT-regulated genes to macrophage polarization in vitro and in vivo, as well as to the development or prevention of in vivo inflammatory responses where deregulated macrophage polarization contributes to pathology. Our results might provide an starting point for the development of novel anti-inflammatory or anti-fibrosis strategies targeting signaling pathways or genes specifically regulated by activin A, MMP12 or 5HT.

Biomolecules & Cell D.
Molecular Biomedicine
Angeles Domínguez Soto