Tumor Necrosis Factor (TNF) Receptor Shedding Controls Thresholds of Innate Immune Activation That Balance Opposing TNF Functions in Infectious and Inflammatory Diseases

Abstract

Tumor necrosis factor (TNF) is a potent cytokine exerting critical functions in the activation and regulation of immune and inflammatory responses. Due to its pleiotropic activities, the amplitude and duration of TNF function must be tightly regulated. One of the mechanisms that may have evolved to modulate TNF function is the proteolytic cleavage of its cell surface receptors. In humans, mutations affecting shedding of the p55TNF receptor (R) have been linked with the development of the TNFR-associated periodic syndromes, disorders characterized by recurrent fever attacks and localized inflammation. Here we show that knock-in mice expressing a mutated nonsheddable p55TNFR develop Toll-like receptor–dependent innate immune hyperreactivity, which renders their immune system more efficient at controlling intracellular bacterial infections. Notably, gain of function for antibacterial host defenses ensues at the cost of disbalanced inflammatory reactions that lead to pathology. Mutant mice exhibit spontaneous hepatitis, enhanced susceptibility to endotoxic shock, exacerbated TNF-dependent arthritis, and experimental autoimmune encephalomyelitis. These results introduce a new concept for receptor shedding as a mechanism setting up thresholds of cytokine function to balance resistance and susceptibility to disease. Assessment of p55TNFR shedding may thus be of prognostic value in infectious, inflammatory, and autoimmune diseases.

Tumor necrosis factor receptor I from patients with tumor necrosis factor receptor–associated periodic syndrome interacts with wild‐type tumor necrosis factor receptor I and induces ligand‐independent NF‐κB activation

“…Therefore, in TRAPS patients, a proinflammatory event triggered by an environmental factor (such as infection [28,29], cancer [30,31], and drug toxicity [32]) that can up-regulate TNFRI expression will have an overall proinflammatory and antiapoptotic effect, because in the case of the T50K variant, which is capable of sustaining inappropriate NF-B activation, this will result in persistent production of proinflammatory mediators including TNF itself. A similar proinflammatory outcome has been shown in a mouse model of TRAPS (33). Importantly, upregulation of TNFRI in the CNS is well documented and has been linked with ischemic preconditioning (34), viral infection (35,36), and peripheral nerve injury (37).…”

Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome

“…Mice homozygous for TRAPS-associated TNFR1 mutations phenocopy TNFR1-deficient mice in their resistance to LPS-induced sepsis and lack of germinal centers and follicular dendritic cell networks in the spleen. The T50M and C33Y TNFR1-mutant mice that model TRAPS do share some similarities with mice engineered to delete the cleavage site of TNFR1 (33), such as hyperresponsiveness to LPS. However, there are a number of important differences, because the cleavage-defective TNFR1 protein still functions as a surface receptor for TNF, whereas the TRAPS mutant TNFR1 does not.…”

Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium

“…The magnitude of an inflammatory response not only depends on TNF dosage but also on the amount of available p55TNFR, a mechanism which is also applied in pathophysiology by shedding of the p55TNFR (46). Halving the amount of p55TNFR leads to a halving of the concentration of multiple (n) toxic inflammatory mediators, such as IL-1, IFN-β, IL-17 and others, identified previously (24-28), leading to a robust (2 n ) combined protection against TNF in Tnfrsf1a +/-mice.…”