SHP-1 (PTPN6) Keeps the Inflammation at Bay: Limiting IL

RESEARCH HIGHLIGHT

SHP-1 (PTPN6) keeps the inﬂammation at bay: limiting IL-1α-mediated neutrophilic dermatoses by preventing Syk kinase activation

Ren-In You1 and Ching-Liang Chu2

Cellular & Molecular Immunology (2017) 14, 881–883; doi:10.1038/cmi.2017.59; published online 10 July 2017

Autoinflammatory syndrome (AIS) is (treatment with IL-1R inhibitor or anti- autoinflammatory diseases, but their life characterized by periodic inflammation IL-1β mAb) significantly reduced disease span could be prolonged to 6 to in the absence of infection, autoantibo- progression and induced sustained 8 months. Interestingly, hypomorphic dies or self-reactive lymphocytes. There- remission in a substantial number of Ptpn6spin (spontaneous inflammation, fore, AIS has defining characteristics that patients.1 Unfortunately, some patients with a Y208N missense mutation in the differ from those of autoimmune dis- still have poor responses to these thera- carboxy terminus) mice can survive for 1 eases. The sterile inflammation observed pies, and their diseases progress with year and display symptoms that resemble in AIS is likely caused by the dysregula- multi-organ inflammation. Thus, scien- those of neutrophilic dermatoses in tion of the innate immune system. How- tists continue to search for new strategies human.3 Therefore, additional genetic ever, the etiologies and physiopathologies with higher efficiency for AIS patients. and functional studies of PTPN6 have of these autoinflammatory disorders Neutrophilic dermatoses, including been facilitated by using these remain ambiguous. Uncontrolled inter- Sweet’s syndrome, pyoderma gangreno- viable mice. leukin (IL)-1 biosynthesis, which is sum and subcorneal pustular dermatosis, Previous studies have shown that the initiated by danger signals in the inflam- are a group of inherited AISs that present cutaneous inflammation in PTPN6- masome or via nucleic acid-sensing path- with excessive neutrophil infiltration in deficient mice is driven by neutrophils.4 ways, has been suggested to have a the skin lesions. In past years, the muta- The Kanneganti group at St. Jude Chil- critical role in AISs such as Behçet’s tion of Ptpn6 gene, which encodes a dren’s Research Hospital has a series disease, Familial Mediterranean fever phosphatase PTPN6 (protein tyrosine of publications that explore this and Cryopyrin-associated periodic syn- phosphatase nonreceptor type 6) or autoinflammatory skin disease using drome. In addition, other proinflamma- SHP-1 (Src homology region 2 (SH2) mouse models. They reported that tory cytokines, including TNF-α, Type-I domain-containing protein phospha- Ptpn6SpinIl1a− / − mice, but not Ptpn6Spi- interferons and IL-18, have been impli- tase), has been linked to not only nIl1b− / − mice, ablate the symptoms of cated in organ-specificinflammation in neutrophilic dermatoses but also auto- dermatoses.5 Their findings suggest an AISs. In clinical studies, colchicine and immune diseases and hematological unknown regulation of the IL-1α path- anti-TNF-α mAbhavebeenusedtotreat malignancies in humans.2 In mice, sev- way that is involved in inflammatory AIS patients, and IL-1 blockade therapies eral Ptpn6 mutants have been identified skin disease. In a recent study,6 the and characterized. A loss of PTPN6 in Kanneganti group further dissected the mice (motheaten, Ptpn6me/me) results in innate immune factors that may be 1Department of Laboratory Medicine and Bio- severe systemic inflammation and death correlated to the disease incidence using technology, Tzu Chi University, Hualian, Taiwan, by 3 to 4 weeks of age. Compared genetic tools and ruled out the require- 2 China and Graduate Institute of Immunology, to Ptpn6me/me mice, Ptpn6me-v/me-v ment of TLRs, TRIF, NODs, RIPK2, College of Medicine, National Taiwan University, Taipei, Taiwan, China (motheaten-viable, a T-to-A transversion type-I IFN, STING, integrin-signaling Correspondence: Professor C-L Chu, Graduate at a splice consensus site) mice also axes and caspase-1/-8 for inflammatory Institute of Immunology, College of Medicine, develop myeloproliferative disease but skin disease. In addition, a bone marrow National Taiwan University, 5F, No1, Sec 1, α Jen-Ai Road, Taipei 10051, Taiwan, China. die at ~ 9 to 10 weeks of age. However, transfer study revealed that IL-1 is meb2/meb2 E-mail: [email protected] Ptpn6 (insertion of a B2 element synthesized by the radioresistant (non- Received: 5 June 2017; Accepted: 6 June 2017 into exon 6) mice present with hematopoietic) cells but that IL-1R is SHP-1 (PTPN6) keeps the inflammation at bay R-I You and C-L Chu

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Steady state Inflammation (SHP-1 defect) Skin microbiota Skin microbiota

MyD88 MyD88 IL-1R Non-hematopoietic IL-1R Non-hematopoietic cells cells IL-1α IL-1α

IL-1R Neutrophil IL-1R Neutrophil

SYK SYK SYK Y180 P P MyD88 MyD88 Y278 SHP-1 P RIPK1 RIPK1 TAK1 spin TAK1 Tnf me/me Ptpn6 Gcsf Ptpn6 (spin)

Figure 1 SHP-1 (PTPN6) prevents IL-1α-driving inflammatory skin diseases by inhibiting Syk-dependent MyD88 phosphorylation in IL-1R signaling. In steady state, IL-1R in neutrophils cannot respond to IL-1α, which is produced by skin microbiota-stimulated non-hematopoietic cells, because SHP-1 inactivated SYK and stops the IL-1R signaling. When SHP-1 is deficient (me/me) or mutated (spin), the active SYK can phosphorylate MyD88 and then recruit RIPK1 and TAK1 to activate downstream signaling and promote the generation of proinflammatory cytokines. Thus, the defect of SHP-1 results in neutrophilic inflammation in skin. Gcsf, granulocyte colony-stimulating factor; IL-1α, interleukin-1α; IL-1R, IL-1 receptor; me, motheaten; MyD88, myeloid differentiation primary response gene 88; P, phosphorylation; PTPN6, protein tyrosine phosphatase nonreceptor type 6; RIPK1, receptor interacting protein kinase 1; SHP-1, SH2 domain-containing protein phosphatase; spin, spontaneous inflammation; SYK, spleen tyrosine kinase; TAK1, tumor growth factor-β activated kinase 1; Y, tyrosine. TNF, tumor necrosis factor. (Drawn by Mr Hsuan-Chao Lin, Graduate Institute of Immunology, National Taiwan University, Taiwan).

necessary in both radioresistant and hormones or infection.7 Although the self-activation or self-amplification beha- hematopoietic cells for disease progres- biogenesis and secretion pathways of vior because IL-1R expression is neces- sion. Moreover, they demonstrated that IL-1α remain poorly defined, the dis- sary in radioresistant cells for disease the expression of myeloid differentiation tinctive role of IL-1α in the inflamma- progression. Although both myeloid primary response gene 88 (MyD88), tory process has been extensively and radioresistant cells require MyD88 receptor interacting protein kinase 1 explored, especially in inflammatory for autoinflammation, it is not clear (RIPK1), tumor growth factor-β acti- and malignant human skin diseases.8 whether the MyD88-dependent IL-1R vated kinase 1 (TAK1) and spleen tyr- Importantly, the Kanneganti group has pathway in myeloid cells can be osine kinase (Syk) in myeloid cell- shown that IL-1α produced by non- utilized in the IL-1α-producing non- specific IL-1R signaling is critical to hematopoietic cells is essential for the hematopoietic cells. provoke inflammatory skin disease in development of neutrophilic inflamma- The regulation of cell death signaling Ptpn6spin mice. Furthermore, the phos- tion in the footpad. They postulated that pathways has been implicated in the phorylation of MyD88 by Syk is essential microbiota primes IL-1α expression in pathogenesis of inflammatory diseases. to activate IL-1R downstream signaling. the non-hematopoietic compartment to RIPK1 has been found in signaling Thus, they concluded that the main promote autoimmunity because antibio- downstream of many receptors to induce function of PTPN6 is to inhibit Syk- tic treatment prevents the onset of skin cell death via its kinase activity or to dependent MyD88 phosphorylation by disease in Ptpn6spin mice.6 However, it is modulate inflammatory signaling and inactivating Syk, which prevents IL-1α- not known how microbiota triggers cell survival via its kinase-independent mediated autoinflammation in the skin IL-1α production in these cells because scaffold functions. RIPK1 is also critical (Figure 1). most innate signaling axes in sensing for the regulation of Fas-associated death IL-1α is known as a proinflammatory microbes, such as TLRs, NODs and domain protein (FADD)-caspase-8- cytokine and is generally produced by interferons, are likely unrelated to dependent apoptosis and RIPK3-mixed non-hematopoietic cells, such as epithe- inflammation in Ptpn6spin mice. More- lineage kinase such as (MLKL)-depen- lial cells, fibroblasts and stromal cells, in over, it is important to determine dent necroptosis.9 Thus, the Kanneganti response to cell death, oxidative stresses, whether the IL-1α–IL-1R axis has a group demonstrated that RIPK1, but not

Cellular & Molecular Immunology SHP-1 (PTPN6) keeps the inﬂammation at bay R-I You and C-L Chu

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RIPK3, critically mediates IL-1α produc- opposite immune responses should be 3 Croker BA, Lawson BR, Rutschmann S, tion by hematopoietic cells and then further investigated. In other studies, Syk Berger M, Eidenschenk C, Blasius AL et al. Inflammation and autoimmunity caused by a drives wound-induced tissue damage has also been reported to modulate TLR SHP1 mutation depend on IL-1, MyD88, and and inflammatory skin disease in signaling via mechanisms that are differ- a microbial trigger. Proc Natl Acad Sci USA Ptpn6Spin mice using fetal liver chimera ent from the regulation of posttranscrip- 2008; 105:15028–15033. studies.5 More recently, genetic evidence tional modification of MyD88 in myeloid 4 Abram CL, Roberge GL, Pao LI, Neel BG, Lowell CA. Distinct roles for neutrophils and fi 14 was provided to further con rm the role cells. In B cells, Syk activation triggered dendritic cells in inflammation and autoim- of RIPK1 scaffold function, but not by TLR4 ligand is dependent on BCR.15 munity in motheaten mice. Immunity 2013; RIPK1 kinase activity or RIPK3-MLKL- Accordingly, Syk may be distinctly regu- 38:489–501. fl 5 Lukens JR, Vogel P, Johnson GR, dependent necroptosis, in the autoin am- lated in different MyD88-dependent sig- Kelliher MA, Iwakura Y, Lamkanfi M et al. spin mation that is observed in Ptpn6 mice. naling pathways and in different cell RIP1-driven autoinflammation targets Furthermore, TAK1 was shown to be types, as suggested by the distinct roles IL-1alpha independently of inflammasomes involved with RIPK1-dependent inflam- of neutrophils and dendritic cells in and RIP3. Nature 2013; 498:224–227. 4 6 Gurung P, Fan G, Lukens JR, Vogel P, mation and disease progression in motheaten mice. Tonks NK, Kanneganti TD. Tyrosine kinase spin Ptpn6 mice, which suggests a new In summary, the Kanneganti group has SYK licenses MyD88 adaptor protein to target gene in IL-1R signaling. Because suggested several therapeutic strategies to instigate IL-1alpha-mediated inflammatory – TAK1 is activated by Lys63-linked ubi- treat skin autoinflammatory diseases, disease. Immunity 2017; 46:635 648. α 7 Di Paolo NC, Shayakhmetov DM. Interleukin quitin (K63-Ub) chains after IL-1 including IL-1 -neutralization approaches 1alpha and the inflammatory process. Nat stimulation,10 it would be interesting to and therapies that target the RIPK1– Immunol 2016; 17:906–913. clarify whether K63-Ub can interact with TAK1 signaling axis, SYK and MyD88 8 Bou-Dargham MJ, Khamis ZI, Cognetta AB, Sang QA. The role of interleukin-1 in inflam- PIPK1 in IL-1R signaling. phosphorylation. SYK inhibitors have matory and malignant human skin diseases Acriticalfinding from their study is been developed to treat autoimmune and the rationale for targeting interleukin- that Syk promotes MyD88 phosphoryla- rheumatic diseases.16 It seems feasible to 1alpha.Med Res Rev 2017; 37:180–216. tion and provokes skin inflammation in apply these inhibitors in AIS therapy. 9 Kondylis V, Kumari S, Vlantis K, Pasparakis M. Ptpn6spin The interplay of IKK, NF-kappaB and RIPK1 mice. It has been established However, approaches that target RIPK1 signaling in the regulation of cell death, that Syk is involved in many signaling should be considered carefully because tissue homeostasis and inflammation. pathways that are initiated from various RIPK1 kinase activity is not required for Immunol Rev 2017; 277: 113–127. surface receptors. Therefore, Syk has a key disease progression. Furthermore, it may 10 Cohen P, Strickson S. The role of hybrid fl fi ubiquitin chains in the MyD88 and other role in in ammatory responses induced be bene cial to design a strategy to innate immune signalling pathways. Cell by the activation and migration of mye- prevent MyD88 phosphorylation in Death Differ 2017; 24:1153–1159. loid cells.11 Although Syk has been shown IL-1R signaling. However, this strategy 11 Futosi K, Mocsai A. Tyrosine kinase signaling pathways in neutrophils. Immunol Rev to associate with TNF receptor-associated could likely be complicated due to various 2016; 273:121–139. factor-6 (TRAF-6) after IL-1 stimulation downstream effects that result from dif- 12 Yamada T, Fujieda S, Yanagi S, Yamamura H, in nasal fibroblast lines,12 their study is ferent MyD88 phosphorylation patterns. Inatome R, Yamamoto H et al. IL-1 induced the first to demonstrate the involvement In addition to these molecules, phospha- chemokine production through the associa- tion of Syk with TNF receptor-associated ofSykinIL-1Rsignalinginmyeloidcells. tidylinositol phosphate kinase type Ic factor-6 in nasal fibroblast lines. J Immunol However, it is not known how IL-1α (PIPKIc), which interacts with PTPN6, 2001; 167: 283–288. treatment can activate Syk, and whether regulates neutrophil migration to inflam- 13 Han C, Jin J, Xu S, Liu H, Li N, Cao X. Integrin CD11b negatively regulates TLR- Src kinases and ITAM-containing adap- matory tissue and could be a potential fl 11 17 triggered in ammatory responses by activat- ters are required. In addition, it remains target. We hope that researchers will ing Syk and promoting degradation of to be clarified whether Syk-dependent reveal more pathogenic mechanisms of MyD88 and TRIF via Cbl-b. Nat Immunol MyD88 phosphorylation can occur in AIS and then find a critical target to 2010; 11:734–742. 14 Yi YS, Son YJ, Ryou C, Sung GH, Kim JH, other MyD88-dependent signaling path- develop an effective therapy in the future. Cho JY. Functional roles of Syk ways. Han et al. illustrated that Syk, which in macrophage-mediated inflammatory is activated by CD11b integrin, can phos- CONFLICT OF INTEREST responses. Mediat Inflamm 2014; 2014: phorylate MyD88 in TLR signaling, but The authors declare no conflict of interest. 270302. 15 Schweighoffer E, Nys J, Vanes L, Smithers N, the phosphorylation site of MyD88 Tybulewicz VLJ. TLR4 signals in B lympho- (Tyr227) is different from that in IL-1R cytes are transduced via the B cell antigen signaling (Tyr180/278), as shown here. receptor and SYK. JExpMed2017; 214: Another different feature from IL-1R 1 Shwin KW, Lee CR, Goldbach-Mansky R. 1269–1280. 16 Deng GM, Kyttaris VC, Tsokos GC. 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