New breakthroughs in TNF biology

19 September 2013
Two new stories from the group of Claude Libert (VIB Department for Molecular Biomedical Research, UGent) increase our knowledge about the mechanism of TNF release, the role of the gutin TNF’s acute toxicity and the value of TNFR1 as adrug target.TNF is a well-validated drug targetin inflammatory disorders.

Is there still room for improvement?
Claude: Absolutely. A significant fraction of patients on anti-TNF treatments develop side-effects,which are likely due to the fact that they inhibit signaling through both TNF receptors, the inflammatory TNFR1 and the immune-modulating TNFR2. Specific inhibition of TNFR1 looks like a promising alternative as this leaves the beneficial TNFR2 signaling intact. In theJCI paper we show that TNFR1 is an ideal drug target because small reductions in TNFR1 expression or availability (genetic or therapeutic interventionsusing antibodies) have robust protective effects against the toxicity of TNF.

Is it known which cells TNFR1 should target?
This, too, was addressed in the JCI paper.Working closely with George Kollias (Institute forImmunology, Greece), who produced conditional TNFR1 knockout and reactivation mutant mice, we found that TNF’s systemic toxicity is essentially mediated by intestinal epithelial cells, and linked with permeability of the gut barrier. Circumstantial evidence of a link between damage to gut integrity and general toxicity had been shown before, but our new data are real proof that the gut is an immediate and life/death-determining target of TNF.The exact process that TNF sets in motion in the gut (cell death, ER stress, and others) are under investigation right now, as well as the therapeutic consequences for TNF-mediated diseases.

Is the gut responsive to TNF or a production place of TNF?
TNF plays a crucial role in autoimmune disorders, but also in endotoxemia and other sepsis-like
conditions. We found that several members of the matrix metalloproteinase family (MMPs) play
an essential role in these diseases. MMP13, a collagenase, was identified as an essential player. MMP13 knockout mice showed protection against endotoxemia-induced lethality and this was associated with lower TNF production and less inflammation-induced gut permeability. The latter two observations were found to be strongly linked as MMP13 was able to proteolytically activate pro-TNF into mature TNF, specifically in the gut. Classically, TNF maturation is performed by a protease called TACE (TNF alpha converting enzyme), but our data show that MMP13 is capable
of similar direct activity. These data certainly suggest that MMP13 is an important drug target in
diseases in which TNF is implicated.

Van Hauwermeiren et al.
J. Clin. Invest, 2013

Vandenbroucke et al.
EMBO Mol. Med., 2013

​From left to right: Claude Libert, Roos Vandenbroucke & Filip Van Hauwermeiren