Macrophages are dynamic and heterogeneous cells that can be divided into specific,
phenotypic subsets. Based on Th1/Th2 polarization concept they are referred to as proinflammatory
classical M1 (IL-12high, IL-23high, IL-10low) macrophages and anti-inflammatory
M2 (IL-12low, IL-23low, IL-10high) macrophages. In contrast to T lymphocyte subsets, the
transcription factor(s) underlying macrophage polarization remain largely unknown.
My research has highlighted the importance of Interferon regulatory factor 5 (IRF5) for
establishing the pro-inflammatory M1 macrophage phenotype. I was able to show that high
expression of IRF5 is characteristic of M1 macrophages, in which it transcriptionally
regulates M1-specific cytokines, chemokines and co-stimulatory molecules. Consequently,
the depletion of IRF5 in human M1 macrophages results in down-regulation of M1-specific
cytokines and further evidence for a role of IRF5 in effective immunity stems from my work
using an in vivo model of polarizing inflammation. IRF5 deficient mice showed a significant
reduction in serum levels of M1-specific cytokines compared to wild-type littermate controls.
Therefore, the suppression of macrophage function via inhibition of IRF5 provides a new
approach to attenuate the inflammatory response.
Tumor necrosis factor (TNF) plays an essential role in the host defence against infections
but is a major factor in the pathogenesis of chronic inflammatory diseases. The expression
of TNF is therefore tightly regulated. I was able to demonstrate that IRF5 is not only
involved in the induction of human TNF gene expression but also crucial for the late phase
secretion of TNF by human myeloid cells. IRF5 is using a complex molecular mechanism to
control the TNF gene with two spatially separated regulatory regions (5‟ upstream and 3‟
downstream of the gene) and two independent modes of action (direct DNA binding and
formation of IRF5/RelA complex) being involved. The manipulation of the IRF5/RelA
interaction could be a putative target for cell-specific modulation of TNF gene expression.