IL-33 Shifts the Balance from Osteoclast to Alternatively Activated Macrophage Differentiation and Protects from TNF-α–Mediated Bone Loss

Abstract

IL-33 is a new member of the IL-1 family, which plays a crucial role in inflammatory response, enhancing the differentiation of dendritic cells and alternatively activated macrophages (AAM). Based on the evidence of IL-33 expression in bone, we hypothesized that IL-33 may shift the balance from osteoclast to AAM differentiation and protect from inflammatory bone loss. Using transgenic mice overexpressing human TNF, which develop spontaneous joint inflammation and cartilage destruction, we show that administration of IL-33 or an IL-33R (ST2L) agonistic Ab inhibited cartilage destruction, systemic bone loss, and osteoclast differentiation. Reconstitution of irradiated hTNFtg mice with ST2−/− bone marrow led to more bone loss compared with the chimeras with ST2+/+ bone marrow, demonstrating an important endogenous role of the IL-33/ST2L pathway in bone turnover. The protective effect of IL-33 on bone was accompanied by a significant increase of antiosteoclastogenic cytokines (GM-CSF, IL-4, and IFN-γ) in the serum. In vitro IL-33 directly inhibits mouse and human M-CSF/receptor activator for NF-κB ligand-driven osteoclast differentiation. IL-33 acts directly on murine osteoclast precursors, shifting their differentiation toward CD206+ AAMs via GM-CSF in an autocrine fashion. Thus, we show in this study that IL-33 is an important bone-protecting cytokine and may be of therapeutic benefit in treating bone resorption.

Severe Neutrophil-Dominated Inflammation and Enhanced Myelopoiesis in IL-33–Overexpressing CMV/IL33 Mice

“…Consistent with previous reports (14,25,27,28), the addition of rmIL-33 to BMG cultures indeed induced production of G-CSF, but also of GM-CSF (D. Talabot-Ayer, C. Gabay, and G. Palmer, unpublished observations) and led to the emergence of a population of macrophage-like cells, contrasting with the preferential neutrophil expansion observed in CMV/IL33 mice in vivo. It is conceivable that IL-33 acts as a general activator of myelopoiesis, by directly or indirectly enhancing the proliferation of myeloid precursors, but that the final polarity of cell differentiation directing engagement into the neutrophil, macrophage, or eosinophil lineages in vivo will be influenced by the local and systemic contexts and cytokine milieu.…”

“…It is conceivable that IL-33 acts as a general activator of myelopoiesis, by directly or indirectly enhancing the proliferation of myeloid precursors, but that the final polarity of cell differentiation directing engagement into the neutrophil, macrophage, or eosinophil lineages in vivo will be influenced by the local and systemic contexts and cytokine milieu. This idea is further supported by published data documenting highly diverse effects of IL-33 on myeloid cell differentiation in BM cultures, according to the culture conditions used (14,15,(25)(26)(27)(28)(29)53).…”

“…In the mouse, an excess of IL-33 activity, caused by systemic or local injection of the recombinant protein (8,(14)(15)(16)(17)(18)(19)(20)(21) by ubiquitous or tissue-specific transgenic overexpression (22,23), or by increased release of the endogenous protein because of removal of its nuclear localization domain (24), was linked to enhanced eosinophil accumulation, eosinophilic organ infiltration, inflammation (8,14,18,(22)(23)(24), basophil expansion (15), or recruitment and activation of neutrophils (16,17,(19)(20)(21). The addition of recombinant IL-33 to cultured mouse bone marrow (BM) cells in different experimental settings promoted cell viability, proliferation, production of myeloid growth factors, and/or modulated cell differentiation (14,15,(25)(26)(27)(28)(29). Furthermore, ST2 expression was described on human and mouse hematopoietic precursor cells, suggesting that IL-33 might exert direct effects on hematopoietic progenitors (30,31).…”

Effects of inflammatory and anti‐inflammatory cytokines on the bone

“…These two members of the IL-17 family of cytokines have pro-inflammatory functions in a variety of animal models of inflammatory disease [41]. There actual role in human inflammatory disease remains to be defined, and so far, only preliminary evidence for an anti-inflammatory effect of specific inhibitors of IL-17 exists for disease such as rheumatoid arthritis.…”

The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

“…In CVB3 infection, the resistance of female mice to myocarditis is associated with the induction of type II cytokines and alternatively activated macrophages (M2) (7). We have previously reported that the recently discovered cytokine, IL-33, is a potent inducer of type II cytokines and M2 (8,9). We therefore investigated the role of IL-33 in CVB5-induced pancreatitis.…”