TNF signaling. TNFα binds to TNFR2, which
may lead to oligomerization of ligand-receptor complexes, helping to propagate signaling. Some regulators of TNF family receptor
signaling are listed.
PGRN bound to TNFR1 and TNFR2 with
nanomolar affinity and blocked interaction
with TNFα. PGRN also inhibited inflammation in disease models that depend on TNFα.
PGRN-deficient mice are hypersensitive to
arthritis (induced by collagen), and treatment
with PGRN reduced clinical and histological
features of this disorder. In a model of systemic inflammation and arthritis (driven by
human TNFα), PGRN-deficient mice developed more severe disease, and treatment with
PGRN slowed arthritis progression.
The effects of PGRN may be complicated
by its cleavage into GRNs. No individual
GRN domain of PGRN bound to TNFR2,
suggesting that the proinflammatory effects
of GRNs may be mediated through other
receptors. However, strong binding to TNFR2
was observed with a fusion of three partial
GRN subunits. This fusion protein, called
antagonist of TNF-TNFR signaling via targeting to TNF receptors (Atsttrin), exhibited
more potent anti-inflammatory activity than
PGRN, perhaps because it does not contain
any complete GRN domains that have proinflammatory function.
Some aspects of how PGRN exerts its
anti-inflammatory effects remain unclear.
Tang et al. determined that the effects of Atsttrin in collagen-induced arthritis depend on
TNFR2. However, PGRN deficiency also
enhanced disease in mice that overexpress
human TNFα, which is thought to interact
solely with mouse TNFR1. Studies with mice
lacking PGRN and one or both TNF receptors
may resolve these discrepancies.
The extracellular regions of TNF recep-
tors are elongated structures with multiple
cysteine-rich repeat domains (CRDs). TNF
family ligands bind to receptors in a hetero-
hexameric 3:3 complex in which each recep-
tor subunit contacts two adjacent ligand sub-
units (see the figure) typically via CRD2
and CRD3, the “stalk” of the receptor. By
contrast, the opposite side of the amino-
terminal CRD1 contains the preligand asso-
ciation domain (PLAD), which mediates
homotypic interactions among receptor
chains and may also stabilize and propagate
ligand-receptor contacts, thus producing
higher-order oligomers critical for recep-
tor signaling (8–11). Although interactions
between receptors through the PLAD
positively influence signaling, bind-
ing of decoy receptors or engineered
soluble receptor homologs to the
PLAD disrupts signaling by the tar-
geted receptor (12, 13).
1. W. Tang et al., Science 332, 478 (2011);
2. X. Valencia et al., Blood 108, 253 (2006).
3. Y. Tada et al., Clin. Immunol. 99, 325 (2001).
4. L. Mori, S. Iselin, G. De Libero, W. Lesslauer, J. Immunol.
157, 3178 (1996).
5. M. Cruts et al., Nature 442, 920 (2006).
6. J. Zhu et al., Cell 111, 867 (2002).
7. F. Yin et al., J. Exp. Med. 207, 117 (2010).
8. F. K. Chan et al., Science 288, 2351 (2000).
9. R. M. Siegel et al., Science 288, 2354 (2000).
10. Y. Mukai et al., Sci. Signal. 3, ra83 (2010).
11. R. M. Siegel et al., J. Cell Biol. 167, 735 (2004).
12. L. Clancy et al., Proc. Natl. Acad. Sci. U.S.A. 102, 18099
13. G.-M. Deng, L. Zheng, F. K.-M. Chan, M. Lenardo, Nat.
Med. 11, 1066 (2005).