Neuroscience Letters 555 (2013) 171–176 Contents lists available at ScienceDirect Neuroscience Letters jou rn al hom epage: www.elsevier.com/locate/neulet Developmental expression of IL-33 in the mouse brain Grzegorz Wicher a , Ena Husic a , Gunnar Nilsson b , Karin Forsberg-Nilsson a,∗ a Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden b Department of Medicine, Clinical Immunology and Allergy Unit, Karolinska Institutet, Solna 171 76, Stockholm, Sweden h i g h l i g h t s • IL-33 is important in inflammation, but less understood in the normal brain. • We mapped expression of IL-33 in embryonic and postnatal mouse brain. • IL-33 expression peaked during the first three weeks of postnatal life. • Astroctyes and oligodendrocyte precursors expressed IL-33. • IL-33 may thus have a role in the absence of an inflammatory response. a r t i c l e i n f o Article history: Received 27 June 2013 Received in revised form 16 September 2013 Accepted 17 September 2013 Keywords: Alarmin Astrocytes Glia Development Neuroinflammation a b s t r a c t IL-33 has important functions in inflammatory and autoimmune diseases. In the brain, models of exper- imental encephalomyelitis are accompanied by up-regulation of IL-33 expression, and the cytokine is seen as an amplifier of the innate immune response. Little is known, however, about IL-33 the normal brain in adult life, or during development. We have analyzed the expression of IL-33 in the mouse brain during embryonic and postnatal development. Here we report that IL-33 expression was first detected in the CNS during late embryogenesis. From postnatal day 2 (P2) until P9 the expression increased and was strongest in the cerebellum, pons and thalamus, as well as in olfactory bulbs. Expression of IL-33 then became weaker and declined until P23, and it was not present in the adult brain. Both astrocytes and oligodendrocyte precursors expressed IL-33. The vast majority of IL-33 positive cells in the brain displayed nuclear staining, and this was found to be the case also in vitro, using mixed glial cultures. Our data suggest that IL-33 expression is under tight regulation in the normal brain. Its detection during the first three weeks of postnatal life coincides with important parts of the CNS developmental programs, such as general growth and myelination. This opens the possibility that IL-33 plays a role also in the absence of an inflammatory response. © 2013 Elsevier Ireland Ltd. All rights reserved. 1. Introduction The cytokine interleukin 33 (IL-33) was described indepen- dently in 1999 as an unknown protein named DVS27 and in 2003 as a nuclear factor from high endothelial venules (NF-HEV) [1,20]. Classified in 2005 as a new member of the IL-1 cytokine family, this 30 kDa protein with high similarity to IL-18 became known as an “alarmin” with crucial roles in the innate immune response [12,21]. IL-33 binds and signals through a receptor complex consisting of the ST2 receptor and the IL-1R accessory protein [5]. Subsequent intracellular signaling events include activation of the ERK and JNK pathways (reviewed in [19]). The localization of IL-33 is nuclear, and it becomes released by necrotic cells after tissue injury. It has ∗ Corresponding author. Tel.: +46 18 471 41 58. E-mail address: karin.nilsson@igp.uu.se (K. Forsberg-Nilsson). also been shown that IL-33 is involved in transcriptional modula- tion [3]. IL-33 has important functions in inflammatory and autoimmune diseases (e.g. asthma, inflammatory bowel disease, autoimmune hepatitis) modulating and activating a variety of immune signaling pathways [7,9,10,21,23]. In the nervous system, high levels of IL-33 mRNA is followed by IL-33 protein expression in a subset of spinal cord astrocytes after experimental allergic encephalomyelitis [24]. Furthermore, IL-33 expression is induced in vitro in pathogen- stimulated astrocytes and microglia cultures [13,24]. Additionally, IL-33 was reported to induce microglia proliferation in vitro [24]. The developmental expression of IL-33 in the central nervous sys- tem (CNS), however, has not been reported. Here we characterized the expression and anatomical location of the IL-33 protein during prenatal and postnatal mouse brain development, and in differentiating mixed glial cell culture. Our results show that IL-33 is present in the intact, non-inflamed CNS during postnatal development, and opens the possibility that it 0304-3940/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neulet.2013.09.046