Il-1 Inflammation

[Bonifacia Cramm]

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Haematopoietic ageing is marked by a loss of regenerative capacity and skewed differentiation from haematopoietic stem cells (HSCs), leading to impaired blood production. Signals from the bone marrow niche tailor blood production, but the contribution of the old niche to haematopoietic ageing remains unclear. Here we characterize the inflammatory milieu that drives both niche and haematopoietic remodelling. We find decreased numbers and functionality of osteoprogenitors at the endosteum and expansion of central marrow LepR+ mesenchymal stromal cells associated with deterioration of the sinusoidal vasculature. Together, they create a degraded and inflamed old bone marrow niche. Niche inflammation in turn drives the chronic activation of emergency myelopoiesis pathways in old HSCs and multipotent progenitors, which promotes myeloid differentiation and hinders haematopoietic regeneration. Moreover, we show how production of interleukin-1β (IL-1β) by the damaged endosteum acts in trans to drive the proinflammatory nature of the central marrow, with damaging consequences for the old blood system. Notably, niche deterioration, HSC dysfunction and defective regeneration can all be ameliorated by blocking IL-1 signalling. Our results demonstrate that targeting IL-1 as a key mediator of niche inflammation is a tractable strategy to improve blood production during ageing.

E.V.V. initiated the studies and contributed to most of the experiments with help from A.H. for BM fluid isolation and immunophenotyping. S.Y.Z. performed GMP cluster analyses and ELISA assays. A.F.S. performed immunofluorescence and whole-mount staining. S.T.B. performed initial 5-FU analyses. T.T.H. performed cell collection and provided technical assistance. C.A.M. re-analysed all the generated data, contributed to various stromal and molecular analyses and, with help from O.C.O., J.W.S. and P.V.D, completed the chronic IL-1β exposure studies and performed all the analyses of Il1r1-deficient mice. F.J.C-N., X.W. and B.G. prepared and analysed the scRNA-seq samples. E.M.P. prepared the microarray samples. E.V.V. and E.P. designed the initial experiments, and C.A.M. and E.P. revised the experiments. E.V.V., C.A.M. and E.P. wrote and edited the manuscript. C.A.M. and E.P. handled the resubmission.

The host bears the receptors that facilitate recognition of these damage-associated molecular patterns (DAMPs) and/or pathogen-associated molecular patterns (PAMPs) that are not host-derived. These receptors are termed pattern recognition receptors (PRRs) [7]. PRRs directly or indirectly detect infection and/or noxious chemicals, resulting in inflammation that is coupled with the induction of immune responses and a tissue reparative component [8]. The signal transduction triggered by these PRRs leads to the acute inflammatory mediator expressions that regulate the elimination of pathogens and infected cells [9, 10].

IL-1 is a master regulator of inflammation via controlling a variety of innate immune processes [21]. From a historical point of view, IL-1 has a wide range of biological functions, which include acting as a leukocytic pyrogen, a mediator of fever and a leukocytic endogenous mediator, and an inducer of several components of the acute-phase response and lymphocyte-activating factor (LAF) [22, 23]. LAF was later shown to be a macrophage-derived immune mediator acting on T- and B- lymphocytes and was designated as IL-1 in the Second International Lymphokine Workshop held in Switzerland in 1979 [24, 25]. In addition, serum blocking factors in breast cancer patients identified by the leukocyte adherence inhibition test were reported. The serum adherence-promoting factors were regulated by IL-1 [26,27,28]. To date, the tumor microenvironment has been characterized by dominant immunosuppression, being infiltrated by tumor immunosuppressive myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and tumor-associated macrophages (TAMs) [29, 30]. IL-1 is capable of inducing the recruitment of TAMs and MDSCs, which promote tumor development in breast cancer [31].

IL-1β is produced as a 269-AA precursor protein and processed by caspase-1, which is also known as IL-1β-converting enzyme (ICE), activated in inflammasomes, to the C-terminal 153 AA as mature IL-1β [11, 12, 34, 44]. The IL-1β precursor is also processed by other serine proteases [45]. Neutrophils derived from caspase-1-deficient mice release mature IL-1β processed by elastase in response to lipopolysaccharide (LPS) stimulation [46]. The neutrophil proteases, such as elastase, chymases, granzyme A, cathepsin G, and proteinase-3, cleave the IL-1β precursor into a secreted, biologically active form [47,48,49]. These alternatively cleaved forms of functional IL-1β were detected in synovial fluid of a patient with inflammatory polyarthritis and gout [50]. Occasionally, massive neutrophil infiltration appeared in excess-inflammation-damaged tissues and organs, such as in septic shock or systemic inflammatory response syndrome. Thus, the NLRP3 inflammasome-related inflammation induced by a variety of factors described above may be a target of anti-IL-1 therapy [51].

There are two cell surface IL-1 receptors, IL-1R1 and IL-1 type 2 receptor (IL-1R2), a decoy receptor. IL-1 binds to IL-1R1, which requires the formation of a heterodimer with the IL-1 type 3 receptor (IL-1R3) (also known as IL-1RAcP) accompanied by adaptor IL-1 receptor-associated kinase (IRAK) and myeloid differentiation primary response protein 88 (MyD88) [76]. IL-1R1 initiates inflammatory responses when binding to the ligands IL-1α and IL-1β and has been reported to be expressed by T- lymphocytes, fibroblasts, epithelial cells, and endothelial cells. IL-1R2, which does not initiate signal transduction, is expressed in a variety of hematopoietic cells, especially in B- lymphocytes, mononuclear phagocytes, polymorphonuclear leukocytes, and bone marrow cells. Notably, expression levels of IL-1R1 and IL-1R2 are different among the cell types; for example, neutrophils predominantly express IL-1R2. As a result, much higher concentrations of IL-1β are required to activate neutrophils, whereas low concentrations of IL-1β are sufficient to activate endothelial cells. The IL-1R1-mediated signaling pathways also differ according to the cell types [77, 78]. IL-1R3 is a co-receptor for IL-1R1, responsible for signaling after binding ligands IL-1α and IL-1β, and has been reported to be ubiquitously expressed by all cells responsive to IL-1. IL-1R3b is a brain-specific isoform of IL-1R3 generated by alternative splicing, and it has been reported to be expressed in the brain, cerebellum, and spinal cord [79].

Activated IL-1 is incapable of functioning until recognized by cell surface receptors. The complex contains a motif of GTPase activity and activates GTPase-activating protein and protein kinases [80,81,82]. In contrast, IL-1R2 is thought to reduce the biological response to IL-1. The proximity of the two cytoplasmic domains of IL-1R1 and IL-1R3 is thought to initiate signal transduction by the hydrolysis of GTP. This is followed by c-Jun N-terminal kinase (JNK) and p38 MAP kinase [83]. IRAK and tumor necrosis factor (TNF) receptor-associated factor (TRAF) 6 activate NF-κB, as well as p38, JNKs, extracellular signal-regulated kinases (ERKs), and mitogen-activated protein kinases (MAPKs) [84]. The NF-κB activation pathway is dependent on the Iκ-B kinase (IKK) complex, composed of IKKα, IKKβ, and NF-κB essential modulator (NEMO), via associations with TAK1, TAK2, TRAF2, and TRAF6 in the IL-1R1-signaling pathway [85]. These signals play important roles in both acute and chronic inflammation in various diseases [86].

Besides the above diseases, numerous inflammatory diseases related to excess IL-1 signaling have also been identified [112,113,114]. For example, high IL-1β levels in humans and mice result in increased Th17-dominant immunopathology, and IL-1β expression was limited to macrophages and neutrophils, which account for a large proportion of the CD45α cells in the cervix upon Chlamydia muridarum infection [115]. Consequently, IL-1β promotes the differentiation of monocytes into conventional dendritic cells (DCs) and M1-like macrophages and supports the proliferation of activated B- lymphocytes and their differentiation into plasma cells [116,117,118]. IL-1 in combination with IL-2 promoted not only the expansion of NK cells but also CD4+ CD8+ T-lymphocytes [119]. IL-1β generated by activated antigen-presenting cells (APCs) induced type 1 immune responses, which produced CTL and led to the polarization of CD4+ T -lymphocytes towards T-helper cell type 1 (Th1) [120, 121].

Although IL-1 has been well-characterized, IL-18 and other IL-1 family members have been less comprehensively investigated. IL-18 can be processed by caspase-1 and proteinase-3 as well as IL-1β, to be activated [130,131,132]. Considering the pathogenesis of IL-1-related diseases, IL-18 could be involved [133].

Interleukin-1 receptors and inhibitors of IL-1 signaling. a IL-1R1 interacts with both IL-1α and IL-1β and promotes signal transduction, together with its co-receptor IL-1R3 (IL-1RAcP). IL-1Ra is a protein that binds to IL-1R1 but not IL-1R3, and it is as an inhibitor of IL-1 signaling. IL-1R2 is a decoy receptor because it lacks a cytoplasmic segment. b Anakinra is a recombinant form of intrinsic human IL-1Ra. It works as an antagonist of IL-1R1, and it is able to inhibit both IL-1α and IL-1β. c Rilonacept is a recombinant fusion protein including the extracellular protein of human IL-1R1 and IL-1R3 fused with the Fc portion of human IgG1. It binds to both IL-1α and IL-1β with high affinity and has a long-term inhibitory effect. d Canakinumab and MABp1 are monoclonal antibodies against IL-1β and IL-1α, respectively. They bind to and neutralize their targets specifically

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