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IL1R8 Deficiency Drives Autoimmunity- Associated Lymphoma

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IL1R8 Deficiency Drives Autoimmunity- Associated Lymphoma Published OnlineFirst April 24, 2019; DOI: 10.1158/2326-6066.CIR-18-0698 Research Article Cancer Immunology Research IL1R8 Deficiency Drives Autoimmunity- Associated Lymphoma Development Federica Riva1,2, Maurilio Ponzoni3, Domenico Supino2, Maria Teresa Sabrina Bertilaccio4, Nadia Polentarutti2, Matteo Massara2, Fabio Pasqualini2, Roberta Carriero2, Anna Innocenzi3, Achille Anselmo2, Tania Veliz-Rodriguez4, Giorgia Simonetti4, Hans-Joachim Anders5, Federico Caligaris-Cappio4, Alberto Mantovani2,6,7, Marta Muzio4,and Cecilia Garlanda2,6 Abstract Chronic inflammation, including that driven by autoim- opment during the aging of IL1R8-deficient lpr mice, observ- munity, is associated with the development of B-cell lym- ing an increased lymphoid cell expansion that evolved to phomas. IL1R8 is a regulatory receptor belonging to the diffuse large B-cell lymphoma (DLBCL). Molecular and IL1R family, which negatively regulates NF-kBactivation gene-expression analyses showed that the NF-kB pathway À À following stimulation of IL1R or Toll-like receptor family was constitutively activated in Il1r8 / /lpr B splenocytes. members. IL1R8 deficiency is associated with the develop- In human DLBCL, IL1R8 had reduced expression compared ment of severe autoimmune lupus-like disease in lpr mice. with normal B cells, and higher IL1R8 expression was We herein investigated whether concomitant exacerbated associated with a better outcome. Thus, IL1R8 silencing inflammation and autoimmunity caused by the deficiency is associated with increased lymphoproliferation and trans- of IL1R8 could recapitulate autoimmunity-associated lym- formation in the pathogenesis of B-cell lymphomas associ- phomagenesis. We thus monitored B-cell lymphoma devel- ated with autoimmunity. Introduction matory conditions, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, and Sjogren syndrome, are prone to develop The association between chronic inflammation and promotion lymphomas, namely, B-cell non-Hodgkin lymphomas (B-NHL; of malignancy was first described in the nineteenth century (1) refs. 4–7). The mechanisms triggering the transition from benign and is supported by epidemiologic and mechanistic data (2, 3). In B-cell proliferation to malignancy are still only partially defined. particular, patients suffering from certain autoimmune or inflam- Chronic inflammation, antigen stimulation, and B-cell receptor signaling, associated with the inherent genetic instability of lym- phocytes, are known to play a central role in lymphoma devel- 1Department of Veterinary Medicine, University of Milan, Milan, Italy. 2Humanitas opment (8, 9). More specifically, gain-of-function mutations of Research Hospital, Rozzano, Italy. 3Ateneo Vita-Salute and Unit of Lymphoid MYD88 and constitutive activation of NF-kB have emerged fi Malignancies, IRCCS San Raffaele Scienti c Institute; Pathology Unit, San among the most frequently recurring mutations in B-cell lym- Raffaele Scientific Institute, Milano, Italy. 4Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy. 5Medizinische Klinik and phoproliferative diseases (10). Poliklinik IV, Klinikum der Universitat€ Munchen,€ LMU Munchen,€ Germany. Mice homozygous for the lymphoproliferation spontaneous lpr 6Humanitas University, Pieve Emanuele, Italy. 7The William Harvey Research inactivating mutation (Fas ) show systemic autoimmunity, mas- Institute, Queen Mary University of London, London, United Kingdom. sive lymphadenopathy associated with proliferation of aberrant Note: Supplementary data for this article are available at Cancer Immunology T cells, arthritis, and immune complex glomerulonephrosis (11). Research Online (http://cancerimmunolres.aacrjournals.org/). In humans, germline mutations in the FAS gene have been Current address for M.T.S. Bertilaccio: Department of Experimental Therapeu- associated with autoimmune lymphoproliferative syndrome tics, The University of Texas MD Anderson Cancer Center, Houston, Texas; (ALPS; ref. 12), and somatic FAS mutations have been found in current address for G. Simonetti, Biosciences Laboratory, Istituto Scientifico multiple myeloma and B-NHL (4). Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; and IL1R8 (also known as TIR8 or single Ig IL1-related receptor, curent address for F. Caligaris-Cappio, Associazione Italiana per la Ricerca sul SIGIRR) is a member of the interleukin-1 receptor (IL1R) Cancro (AIRC), Milano, Italy. family acting as a negative regulatory receptor (13). IL1R8 inhibits Corresponding Authors: Cecilia Garlanda, Istituto Clinico Humanitas, Via NF-kB and JNK activation following stimulation of IL1R or Manzoni 113, 20089 Rozzano, Italy. Phone: 39-028-224-5115; Fax: 39-028- TLR family members by interfering with the recruitment of TIR 224-5101; E-mail: [email protected]; and Marta Muzio, domain-containing adaptor molecules (14–17). In combination IRCCS San Raffaele Hospital, Milano, Italy, Via Olgettina 60, 20132 Milano, Italy. a Phone: 39-02-26437104; Fax: 39-02-26434575; E-mail: [email protected] with IL18R , IL1R8 also serves as one of the receptor chains for the anti-inflammatory cytokine IL37, thereby activating anti- Cancer Immunol Res 2019;7:874–85 inflammatory responses (18). doi: 10.1158/2326-6066.CIR-18-0698 IL1R8 deficiency leads to uncontrolled activation of IL1R or TLR Ó2019 American Association for Cancer Research. family members and is associated with exacerbated inflammatory 874 Cancer Immunol Res; 7(6) June 2019 Downloaded from cancerimmunolres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst April 24, 2019; DOI: 10.1158/2326-6066.CIR-18-0698 IL1R8 in Autoimmunity-Associated B-cell Lymphoma responses (14, 19) and autoimmunity (16, 20–22). Accordingly, investigators who were blinded to the experimental group. The downregulation of IL1R8 is observed in psoriasis (23). Depending following antibodies were used: anti-B220 (RA3-6B2, Serotec), on the context, IL1R8 is involved in modulating either inflam- anti-Ki67 (SP6, Neo Markers), anti-CD3 (1F4, Bio-Rad), anti- mation-associated tumorigenesis and tumor progression, includ- BCL6 (Rabbit polyclonal, Santa Cruz Biotechnology), anti-BCL2 ing colorectal cancer (19, 24, 25) and chronic lymphocytic leu- (C21, Santa Cruz Biotechnology), and anti-Multiple Myeloma 1/ kemia (CLL; ref. 26), or NK cell–mediated antitumor immune Interferon Regulatory Factor 4 protein (MUM1/IRF4; 3E4, responses in mouse models (27, 28). BioLegend; ref. 31). IL1R8 deficiency in lpr mice is associated with severe lympho- proliferation and autoimmune lupus-like disease (16), due to Tumor transplantation increased dendritic cell (DC) activation and B-cell proliferation in A total of 107 cells (5 Â 106 splenocytes plus 5 Â 106 lymph À À response to TLR7- and TLR9-activating autoantigens or nucleo- node cells) from 10- to 12-month-old Il1r8 / /lpr (n ¼ 8) or þ þ somes (29, 30). Il1r8 / /lpr (n ¼ 7) mice were injected i.p., s.c., or i.v. into C57BL/ À À The involvement of IL1R8 in autoimmunity, and the critical 6J, nude or SCID mice (n ¼ 17 recipients of Il1r8 / /lpr cells; þ þ role of constitutive activation of MyD88-dependent NF-kB n ¼ 16 recipients of Il1r8 / /lpr cells). Recipient animals were activation in B-cell transformation, raised the hypothesis that sacrificed when clinical signs (enlargement of mandibular lymph IL1R8 might be involved in the autoimmunity-associated risk nodes or abdomen) were evident or 12 to 20 months after of developing lymphoma. Here, we show that IL1R8 deficiency transplantation, and organs were collected for histologic and was associated with significantly earlier death and increased molecular analysis. The genotype of several tissues of all recipient susceptibility to lymphoproliferation, which evolved in trans- mice was analyzed for lpr and Il1r8 mutations by PCR (14). plantable diffuse large B-cell lymphoma (DLBCL). Analysis of clonality showed that multiple independent transformation Western blot analysis events occurred in the same host. In humans, IL1R8 was poorly Western blot analysis of purified B-cell lysates (30 mg total expressed in DLBCL cell lines and primary lesions when proteins) was performed with the following antibodies: rabbit compared with peripheral blood or germinal center B cells anti-p100/p52 (CS4882, 1:1,000, overnight at 4), mouse anti- and was associated with better outcome in terms of overall Phospho-p65 (CS3036, 1:1,000, overnight at 4C), rabbit anti- survival, suggesting that IL-1R8 downregulation is a driver of p65 (CS8242, 1:1,000, 2 hours RT; Cell Signaling Technology); lymphomagenesis. anti-beta-actin-HRP (SIGMA A3852, 1:10,000, 2 hours room temperature), followed by anti-rabbit-HRP (Sigma A0545, 1:5,000) or anti-mouse-HRP (Sigma A3682, 1:5,000), using Materials and Methods 10% or 4%–12% gradient precast gels (GenScript). Animals and samples À À IL1R8-deficient (Il1r8 / ) mice were generated as Real-time PCR and real-time PCR array described (14) and backcrossed to the C57BL/6J background Total RNA from mouse spleen-purified B cells, DLBCL cell lines, À À (Charles River Laboratories) up to the F11 generation. Il1r8 / and B cells from healthy donor buffy coats was isolated with a and B6lpr/lpr (Charles River Laboratories) were crossed to generate column-based kit followed by DNAse treatment (Promega; for À À Il1r8 / /lpr mice. Mice were housed in the SPF animal facility of PCR array) or TRI reagent (Sigma-Aldrich; for PCR). RNA was Humanitas Research Hospital
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