Available online 27 March 2024, 101941

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TNF signals via two receptors, TNFR1 and TNFR2, which play contrasting roles in immunity. Most of the pro-inflammatory effects of TNF are mediated by TNFR1, whereas TNFR2 is mainly involved in immune homeostasis and tissue healing, but also contributes to tumour progression. However, all currently available anti-TNF biologics inhibit signalling via both receptors and there is increasing interest in the development of selective inhibitors; TNFR1 inhibitors for autoimmune disease and TNFR2 inhibitors for cancer. It is hypothesised that selective inhibition of TNFR1 in autoimmune disease would alleviate inflammation and promote homeostasis by allowing TNFR2 signalling to proceed unimpeded. Validation of this concept would pave the way for the development and testing of TNF specific antagonists. Another therapeutic approach being explored is the use of TNFR2 specific agonists, which could be administered alone or in combination with a TNFR1 antagonist.

Section snippetsBackground: one cytokine, two receptors

Tumour necrosis factor (TNF) is a major driver of inflammation and contributes to the pathogenesis of numerous chronic diseases. Indeed, biologic TNF inhibitors have now been approved for the treatment of rheumatoid arthritis (RA) [1], ankylosing spondylitis [2,3], Crohn's disease [3], hidradenitis suppurativa [4], juvenile idiopathic arthritis [5], plaque psoriasis [6], polyarticular juvenile idiopathic arthritis [7], psoriatic arthritis [8], ulcerative colitis [9] and uveitis [10].

TNFR2 and regulatory T (Treg) cells

The avoidance of excessive tissue damage during immune and inflammatory responses is achieved partly through the elimination of self-reactive T effector cells in the thymus, and partly through a process of peripheral immune regulation. Treg cells are a subset of lymphocytes that play an indispensable role in maintaining self-tolerance in the periphery by regulating the activity of T effector cells [19]. The importance of Treg cells in homeostasis is underscored by the fact that loss-of-function

TNFR2 and myeloid cells

Monocytes and macrophages express both TNFR1 and TNFR2 and there is a complex interplay between the two receptors affecting their survival and function, in a tissue specific manner [15]. As discussed above, both receptors recruit TRAF2 and cIAPs and it is proposed that activation of TNFR2 may deplete the cytosolic pool of TRAF2 and cIAP1/2, thereby limiting the ability of TNFR1 to stimulate canonical NFκB signalling [35]. Treatment of mice with a TNFR2 agonist was shown to promote the

TNFR2 and tissue repair

Mesenchymal stem cells (MSCs) play an important role in tissue repair and have been used to treat several autoimmune, inflammatory and degenerative disorders [46,47]. The reparative activities of MSCs are amplified by their ability to promote homeostasis, chiefly through the induction of T reg cells. In a recent study, TNFR2 deficiency resulted in reduced MSC colony-forming units and diminished expression of stem cell antigen-1 (Sca-1), CD90, CD105, CD44, and CD73, all of which are

Strategies for promoting TNFR2 signalling

All current TNF inhibitors target the cytokine itself therefore inhibit signalling via both receptors. However, etanercept also blocks lymphotoxin-α [51], though it is unclear whether this contributes to its therapeutic effect. Nguyen and Ehrenstein argue that treatment with adalimumab, but not etanercept, indirectly favours TNFR2 signalling by enhancing the expression of membrane bound TNF, although the mechanism underlying this phenomenon remains to be elucidated [52]. A more direct strategy

Summary

The development of selective agonists and antagonists of TNFR1 and TNFR2 is an exciting area of drug discovery, not only for chronic inflammatory diseases but also for cancer. TNFR1 selective inhibitors offer the prospect of inhibition of inflammation plus the maintenance of homeostatic and pro-healing signalling pathways. However, there is uncertainty over the extent to which TNFR2 signalling will predominate within the inflammatory milieu, given that most of the TNF will be in the soluble

Research Agenda•

A key research goal will be to demonstrate the therapeutic advantages of selective TNF receptor targeting versus inhibition of TNF

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Although most research on TNFR2 has focussed on its immunoregulatory actions, there is growing interest in its role in tissue healing in different scenarios and whether the pathway can be exploited therapeutically.

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The impact of TNFR2 signalling on metabolic reprograming in lymphocytes, and potentially other immune cells, is a matter of growing interest.

CRediT authorship contribution statement

Richard O. Williams: Conceptualization. Felix IL. Clanchy: Conceptualization, Formal analysis, Investigation, Writing – original draft. Yi-Shu Huang: Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft. Wen-Yi Tseng: Conceptualization, Data curation, Formal analysis, Investigation. Trevor W. Stone: Conceptualization, Supervision, Writing – original draft.

Declaration of competing interest

The authors declare that they have no conflict of interest.

Acknowledgements

This work was supported in part by grants from the Ministry of Science and Technology, Taiwan (MOST-104-2911-I-182A-503) and Chang Gung Memorial Hospital (CMRPG2H0261 and CMRPG2J0051).

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