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Inflammasome-Independent IL-1Β Mediates Autoinflammatory Disease in Pstpip2-Deficient Mice

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Inflammasome-Independent IL-1Β Mediates Autoinflammatory Disease in Pstpip2-Deficient Mice Inflammasome-independent IL-1β mediates autoinflammatory disease in Pstpip2-deficient mice Suzanne L. Cassela,b,c,1, John R. Janczya,c, Xinyu Bingd, Shruti P. Wilsonb, Alicia K. Oliviere, Jesse E. Oterof, Yoichiro Iwakurag,h, Dmitry M. Shayakhmetovi, Alexander G. Bassukd, Yousef Abu-Amerj, Kim A. Brogdenk, Trudy L. Burnsd,l, Fayyaz S. Sutterwalaa,b,c,m,1, and Polly J. Fergusond,1,2 aInflammation Program, bDepartment of Internal Medicine, cGraduate Program in Immunology, dDepartment of Pediatrics, eDepartment of Pathology, fDepartment of Orthopedics, kDows Institute for Dental Research and Department of Periodontics, College of Dentistry, and lDepartment of Epidemiology, University of Iowa, Iowa City, IA 52242; gResearch Institute for Biomedical Sciences, Tokyo University of Science Yamasaki 2669, Noda, Chiba 278-0022, Japan; hCore Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan; iDivision of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195; jDepartment of Orthopedics, Washington University School of Medicine, St. Louis, MO 63110; and mVeterans Affairs Medical Center, Iowa City, IA 52241 Edited by Ruslan Medzhitov, Yale University School of Medicine, New Haven, CT, and approved December 13, 2013 (received for review October 3, 2013) Chronic recurrent multifocal osteomyelitis (CRMO) is a human auto- of disease (9). Although it is known that cmo mice have a dysre- inflammatory disorder that primarily affects bone. Missense muta- gulated innate immune system, it is not clear what inflammatory tion (L98P) of proline-serine-threonine phosphatase-interacting pathway is critical for disease. protein 2 (Pstpip2) in mice leads to a disease that is phenotypically Mutations within NLRP3 (also known as NALP3 or cryopyrin) similar to CRMO called chronic multifocal osteomyelitis (cmo). Here are associated with the autoinflammatory Muckle-Wells syn- we show that deficiency of IL-1RI in cmo mice resulted in a significant drome, familial cold autoinflammatory syndrome, and neonatal- reduction in the time to onset of disease as well as the degree of bone onset multisystem inflammatory disease, collectively known as pathology. Additionally, the proinflammatory cytokine IL-1β, but not cryopyrin-associated periodic syndrome (10). These NLRP3 IL-1α, played a critical role in the pathology observed in cmo mice. In mutations result in a constitutively active form of NLRP3 that contrast, disease in cmo mice was found to be independent of the leads to increased inflammasome activation with a resultant in- nucleotide-binding domain, leucine-rich repeat-containing family, crease in secretion of IL-1β (10). A diverse array of agonists has IMMUNOLOGY pyrin domain-containing 3 (NLRP3) inflammasome as well as cas- been identified that are capable of activating NLRP3, which pase-1. Neutrophils, but not bone marrow-derived macrophages, results in the assembly of the NLRP3 inflammasome composed β from cmo mice secreted increased IL-1 in response to ATP, silica, of NLRP3, the adaptor molecule apoptosis-associated speck-like and Pseudomonas aeruginosa compared with neutrophils from WT protein containing a CARD (ASC), and caspase-1 (11). The mice. This aberrant neutrophil response was sensitive to inhibition activation of the inflammasome leads to the activation of caspase- by serine protease inhibitors. These results demonstrate an inflam- 1, with the resultant processing of pro-IL-1β and pro-IL-18 to their masome-independent role for IL-1β in disease progression of cmo mature and secreted forms (12). However, the role of the NLRP3 and implicate neutrophils and neutrophil serine proteases in dis- inflammasome in the pathogenesis of cmo remains unknown. ease pathogenesis. These data provide a rationale for directly tar- Given the evidence that IL-1 is important in the pathogenesis geting IL-1RI or IL-1β as a therapeutic strategy in CRMO. of sterile bone inflammation in humans (3, 4), we investigated the role of IL-1 in the pathogenesis of sterile osteomyelitis in the chronic osteomyelitis | innate immunity cmo mouse. Here we demonstrate that deficiency of IL-1RI (interleukin-1 receptor type I) or IL-1β in cmo mice resulted in hronic recurrent multifocal osteomyelitis (CRMO) is a ster- ile inflammatory disorder that affects children and presents C Significance with bone pain due to sterile osteomyelitis (1). The etiology of the disease is unknown, but it is associated with Crohn disease, inflammatory arthritis, and psoriasis in affected individuals and Chronic recurrent multifocal osteomyelitis (CRMO) is a hu- their close relatives, suggesting a shared pathophysiology and man disorder of the innate immune system that causes bone supporting a genetic contribution to disease (2). There are two inflammation that mimics infectious osteomyelitis. There is autosomal recessive disorders that present with neonatal- or a spontaneous mutant mouse model of the disease that is infant-onset sterile osteitis that are histologically similar to the caused by homozygous mutations in the gene Pstpip2.Our bone disease in CRMO and clinically improve with IL-1 blockade studies show that bone inflammation in this model is me- β (3, 4). Majeed syndrome, caused by mutations in LPIN2, pres- diated by the cytokine IL-1 , but that the disease is in- ents with CRMO, congenital dyserythropoietic anemia, and dependent of the nucleotide-binding domain, leucine-rich sterile neutrophilic dermatosis (5). Deficiency of the IL-1 receptor repeat-containing family, pyrin domain-containing 3 (NLRP3) antagonist (DIRA) is caused by mutations in IL1RN, which encodes inflammasome and caspase-1, which is different from most – the IL-1 receptor antagonist (3), resulting in dysregulation of other IL-1 mediated disorders. Further, we implicate neutrophils the IL-1 pathway. Affected individuals present with neonatal- and neutrophil serine proteases in disease pathogenesis. These data provide a rationale for directly targeting the IL-1 re- onset cutaneous pustulosis, marked elevation of inflammatory β markers, sterile multifocal osteitis, and periostitis (3). ceptor or IL-1 as a therapeutic strategy in CRMO. There are two autosomal recessive murine models of CRMO Author contributions: S.L.C., J.R.J., J.E.O., A.G.B., F.S.S., and P.J.F. designed research; S.L.C., both due to mutations in proline-serine-threonine interacting pro- J.R.J., X.B., S.P.W., A.K.O., J.E.O., K.A.B., F.S.S., and P.J.F. performed research; S.L.C., Y.I., tein 2 (Pstpip2)(6–8). The mutation (L98P) present in the chronic D.M.S., Y.A.-A., F.S.S., and P.J.F. contributed new reagents/analytic tools; S.L.C., J.R.J., X.B., multifocal osteomyelitis (cmo) model results in no detectable ex- A.K.O., J.E.O., A.G.B., T.L.B., F.S.S., and P.J.F. analyzed data; and S.L.C., J.R.J., A.G.B., F.S.S., pression of Pstpip2, a protein expressed predominantly in the cells and P.J.F. wrote the paper. of the myeloid lineage, and leads to disease that resembles hu- The authors declare no conflict of interest. man CRMO (6, 9). The development of osteomyelitis in the cmo This article is a PNAS Direct Submission. mouse is hematopoietically driven and develops in the absence 1S.L.C., F.S.S., and P.J.F. contributed equally to this work. of lymphocytes, consistent with an autoinflammatory mechanism 2To whom correspondence should be addressed. E-mail: [email protected]. www.pnas.org/cgi/doi/10.1073/pnas.1318685111 PNAS Early Edition | 1of6 Downloaded by guest on September 27, 2021 delayed onset of disease and an attenuation of disease severity. IL-1β Deficiency, but Not IL-1α Deficiency, Results in Diminished Bone In contrast, disease progression in cmo mice was found to be Inflammation in cmo Mice. Because both IL-1α and IL-1β signal independent of the NLRP3 inflammasome, and in vitro find- through the IL-1RI we crossed mice deficient in either IL-1α or ings support a role for neutrophil serine proteases in the ab- IL-1β with cmo mice to determine their individual contribution normally increased secretion of IL-1β. Taken together these to cmo pathology. No significant difference in the time to onset data demonstrate an inflammasome-independent role for the IL-1 of disease or the degree of tail bone destruction and inflam- − − pathway in the disease pathogenesis of cmo. mation was observed in cmo.IL-1α / mice compared with con- + − − − trol cmo.IL-1α / mice (Fig. 3 A–C). In contrast, cmo.IL-1β / Results and Discussion mice were significantly protected from developing disease; at − − Pstpip2-Deficient cmo Mice Have Increased Proinflammatory Cytokines 85 d of age only 17% of cmo.IL-1β / mice had developed in Vivo. The role of the IL-1 pathway in the disease pathogenesis clinical signs of disease, in comparison with 88% of control + − of cmo is largely unknown. To determine the contribution of in- cmo.IL-1β / mice (Fig. 3D). Histological analysis of tail bones of − − flammatory mediators in vivo we assessed tissue cytokine levels in cmo.IL-1β / mice at ∼180 d of age revealed structurally normal the tails of symptomatic cmo mice. As expected, WT mice had bone with minimal inflammatory infiltrates (Fig. 3 E and F). − − minimal inflammatory cytokines detected within tail homogenates Although cmo.IL-1β / mice displayed significantly diminished + − (Fig. 1 A and B). IL-1β levels were significantly elevated, whereas disease compared with control cmo.IL-1β / mice they did not − − IL-1α levels also trended toward being increased in cmo mice fully recapitulate the lack of disease observed in cmo.IL-1RI / (Fig. 1A). Because previous studies have demonstrated elevated mice, suggesting that IL-1α and IL-1β may have synergistic serum levels of proinflammatory cytokines in cmo mice, we affects in mediating cmo disease. Alternatively, in addition to investigated these cytokines in tail homogenates.
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