IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity

Molgora, Martina; Bonavita, Eduardo; Ponzetta, Andrea; Riva, Federica; Barbagallo, Marialuisa; Jaillon, Sébastien; Popović, Branka; Bernardini, Giovanni; Magrini, Elena; Gianni, Francesca; Zelenay, Santiago; Jonjić, Stipan; Santoni, Angela; Garlanda, Cecília; Mantovani, Alberto

doi:10.1038/nature24293

Cited by 177 publications

(204 citation statements)

References 42 publications

Supporting

Mentioning

196

Contrasting

Order By: Relevance

“…IL‐1R8 is abundantly expressed in NK cells and it keeps under control their maturation and cytotoxic activity by inhibiting the effects of IL‐18, a cytokine of the IL‐1 family with a major role in NK cell development and function . Indeed, genetic blockade of IL‐1R8 in the mouse results in strong NK‐mediated anti‐tumor and antiviral resistance …”

Section: Regulation In the Il‐1r Familymentioning

confidence: 99%

The family of the interleukin‐1 receptors

Boraschi

Italiani

Weil

et al. 2017

Immunological Reviews

275

225

View full text Add to dashboard Cite

The extracellular forms of the IL-1 cytokines are active through binding to specific receptors on the surface of target cells. IL-1 ligands bind to the extracellular portion of their ligand-binding receptor chain. For signaling to take place, a non-binding accessory chain is recruited into a heterotrimeric complex. The intracellular approximation of the Toll-IL-1-receptor (TIR) domains of the 2 receptor chains is the event that initiates signaling. The family of IL-1 receptors (IL-1R) includes 10 structurally related members, and the distantly related soluble protein IL-18BP that acts as inhibitor of the cytokine IL-18. Over the years the receptors of the IL-1 family have been known with many different names, with significant confusion. Thus, we will use here a recently proposed unifying nomenclature. The family includes several ligand-binding chains (IL-1R1, IL-1R2, IL-1R4, IL-1R5, and IL-1R6), 2 types of accessory chains (IL-1R3, IL-1R7), molecules that act as inhibitors of signaling (IL-1R2, IL-1R8, IL-18BP), and 2 orphan receptors (IL-1R9, IL-1R10). In this review, we will examine how the receptors of the IL-1 family regulate the inflammatory and anti-inflammatory functions of the IL-1 cytokines and are, more at large, involved in modulating defensive and pathological innate immunity and inflammation. Regulation of the IL-1/IL-1R system in the brain will be also described, as an example of the peculiarities of organ-specific modulation of inflammation.

show abstract

Section: Regulation In the Il‐1r Familymentioning

confidence: 99%

The family of the interleukin‐1 receptors

Boraschi

Italiani

Weil

et al. 2017

Immunological Reviews

275

225

View full text Add to dashboard Cite

show abstract

“…IL‐1R8 was also shown to regulate JNK and mTOR phosphorylation in Th17 cells and NK cells, and mTOR phosphorylation driven by IL‐1 or TLR agonists derived from commensal flora in intestinal epithelial cells (Figure ). In these cell types, IL‐1R8 is therefore crucial in the modulation of metabolism, differentiation, cell cycle, and effector functions also in homeostatic conditions.…”

Section: Il‐1r8 (Tir8/sigirr)mentioning

confidence: 98%

“…Our group has recently described that murine and human NK cells express very high levels of IL‐1R8 and that IL‐1R8 is acquired during NK cell differentiation, both in terms of mRNA and protein . IL‐1R8 deficiency was associated with higher frequency and absolute number of mature NK cells in blood, spleen, bone marrow and liver, higher levels of activating NK cell receptors and increased interferon‐γ (IFNγ), granzyme B, Fas ligand expression and degranulation . Bone marrow chimeric and mixed chimeric mice experiments demonstrated that IL‐1R8 directly acts on NK cells regulating IL‐18, which is a key cytokine involved in NK cell activation .…”

Section: Il‐1r8 (Tir8/sigirr)mentioning

confidence: 99%

Tuning inflammation and immunity by the negative regulators IL‐1R2 and IL‐1R8

Molgora

Supino

Mantovani

et al. 2017

Immunological Reviews

Self Cite

View full text Add to dashboard Cite

Interleukin-1 receptor family members (ILRs) and Toll-Like Receptors (TLRs) are key players in immunity and inflammation and are tightly regulated at different levels. Most cell types, including cells of the innate and adaptive immune system express ILRs and TLRs. In addition, IL-1 family members are emerging as key players in the differentiation and function of innate and adaptive lymphoid cells. IL-1R2 and IL-1R8 (also known as TIR8 or SIGIRR) are members of the ILR family acting as negative regulators of the IL-1 system. IL-1R2 binds IL-1 and the accessory protein IL-1RAcP without activating signaling and can be released as a soluble form (sIL-1R2), thus modulating IL-1 availability for the signaling receptor. IL-1R8 dampens ILR- and TLR-mediated cell activation and it is a component of the receptor recognizing human IL-37. Here, we summarize our current understanding of the structure and function of IL-1R2 and IL-1R8, focusing on their role in different pathological conditions, ranging from infectious and sterile inflammation, to autoimmunity and cancer-related inflammation. We also address the emerging evidence regarding the role of IL-1R8 as a crucial checkpoint molecule in NK cells in anti-cancer and antiviral activity and the potential therapeutic implications of IL-1R8 blockade in specific pathological contexts.

show abstract

“…As such, there is intense interest in understanding how these functions are regulated in order to devise novel therapeutic strategies to harness NK cell function in disease. In a recent issue of Nature , a team led by Alberto Mantovani and Cecilia Garlanda have identified a new “checkpoint” or negative regulator of NK cell function known as IL‐1R8 . Their data demonstrate that IL‐1R8 expression by NK cells dampens their response to the inflammatory cytokine IL‐18, and that genetic deletion of Il1r8 unleashes NK cell dependent resistance to hepatic carcinoma, tumor metastasis and cytomegalovirus infection.…”

mentioning

confidence: 99%