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J Immunol 2007; 178:3343-3344; ; doi: 10.4049/jimmunol.178.6.3343 This information is current as http://www.jimmunol.org/content/178/6/3343 of September 24, 2021. Downloaded from

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The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. THE

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Phagocytosing Neisseria with wild-type controls. A src family kinase inhibitor had effects on resting or fMLP-stimulated wild-type mouse or Ϫ Ϫ Ϫ Ϫ ram-negative Neisseria human neutrophils similar to those seen in hck / fgr / species infect mucosal mouse cells. Akt phosphorylation and calcium mobilization G surfaces by attachment were unaffected in mutant mouse cells or human cells treated with to carcinoembryonic Ag-related the inhibitor after fMLP stimulation. The authors conclude that cellular adhesion molecule 3 src family kinases hck and fgr play an essential role in NADPH (CEACAM3). However, human oxidase activation by fMLP-stimulated neutrophils via Vav1 phos- granulocytes readily phagocytose phorylation and activation of p21-activated kinases. CEACAM3-binding bacteria in an opsonin-independent man- ner that requires tyrosine phos- Controlling Bacteremia

phorylation of the ITAM-like sequence in the CEACAM3 cy- Downloaded from toplasmic tail. In an investigation of guanine nucleotide acteremia, or high blood levels of bacteria, is a leading exchange factors that could link CEACAM3 engagement/ cause of death from microbial infections; rapid clear- phosphorylation and stimulation of the small GTPase Rac, B ance of the bacteria increases survival. Alugupalli et al. Schmitter et al. (p. 3797) found that only transfected domi- (p. 3740) studied various strains of mutant mice infected with nant-negative Vav reduced up-take of Neisseria gonorrhoeae by Borrelia hermsii, the causative agent of relapsing fever, to deter-

cotransfected CEACAM in human embryonic kidney cells in mine factors critical to bacteria clearance. Although infected http://www.jimmunol.org/ vitro. Short interfering mRNA specific for Vav2 also decreased mice deficient in Bruton’s tyrosine kinase (Btk) and B1 cells bacterial infection of cells and reduced levels of Rac GTP load- were able to generate the B. hermsii-specific IgM Abs absolutely ing. Cells from mice lacking both Vav1 and Vav2 failed to required to resolve the infection in a T cell-independent man- internalize tagged gonococci unless transfected with a Vav-ex- ner, their relapsing episodes of bacteremia were more severe and pressing vector. Vav2 and CEACAM3 were coimmunoprecipi- their recovery more prolonged than wild-type controls. Mice tated from N. gonorrhoeae-infected cells; the use of ITAM mu- deficient in MyD88, but not mice lacking any of the other three Ϫ Ϫ tants and peptide spot assays established a requirement for TLR adaptor , and TLR2 / mice had severely delayed

interaction between the Vav Src homology 2 domain and phos- and reduced production of anti-B. hermsii IgM Abs compared by guest on September 24, 2021 230 phorylated Tyr in CEACAM3. Primary human granulo- with infected wild-type animals. IgM Ab responses also were Ϫ Ϫ Ϫ Ϫ cytes failed to internalize N. gonorrhoeae if preincubated with a diminished and delayed in infected TLR1 / , TLR4 / , and Ϫ Ϫ dominant-negative Vav fusion . The data demonstrate CD14 / mice. Mice lacking Btk plus MyD88 had popula- that Vav is a direct link between CEACAM3-binding gono- tions of B1a, B1b, and marginal zone B subsets of IgM-se- cocci and Rac GTP stimulation during opsonin-independent creting mature B cells lower than wild-type but equivalent to Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ by human granulocytes. Btk / mice. However, Btk / MyD88 / mice were com- pletely unable to produce IgM Abs to clear B. hermsii infec- tions. The interpretation of the data is that clearance of B. hermsii bacteremia requires both Btk and MyD88 to gener- Neutrophil Responses to fMLP ate IgM Abs in an atypical T cell-independent TLR-driven B nteraction of bacterial or mitochondrial N-formylated cell response. peptides with receptors on neutrophils stimulates activa- I tion of a variety of membrane phospholipids and intracel- ␣ lular kinases involved in signal transduction. However, it is not Allelic Variant of Fc RI known if src family kinases are part of the signaling pathway. ecretory IgA initiates in- Fumagalli et al. (p. 3874) measured reduced superoxide anion ␮ flammatory responses production, transmigration through 1- m pores, F-actin poly- through Fc␣RI ex- merization, and tyrosine phosphorylation of several cellular S pressed on myeloid lineage cells. proteins in fMLP-treated neutrophils from mice deficient for Fc␣RI is often not paired with hemopoietic cell kinase (hck) plus Gardner-Rasheed feline sar- FcR ␥-chain, but the function coma viral oncogene homologue (fgr) compared with wild-type of the unpaired receptor is not cells. Decreased phosphorylations of JNK and the guanine nu- known. Wu et al. (p. 3973) cleotide exchange factor Vav1 also were noted, and no phos- found a common single nucleo- phorylation of two Rac target p21-activated kinases occurred in Ϫ Ϫ Ϫ Ϫ tide polymorphism resulting in replacement of a serine with a resting and fMLP-exposed hck / fgr / mouse cells compared glycine within the cytoplasmic domain of human Fc␣RI. Stim- Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 ulated rat mast cells transfected with the glycine variant were

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؊ ؊ more efficient at mediating intracellular calcium release, in- Apoptosis of IRF-2 / Macrophages duced more degranulation, and had greater IL-6 and TNF-␣ release than cells transfected with the serine variant. Cytokine ogel and colleagues have shown that mice lacking IFN release occurred in stimulated mouse cells transfected with the regulatory factor 2 (IRF-2) survive LPS challenge bet- glycine, but not the serine, containing Fc␣RI that also had a V ter than wild-type animals and have higher numbers transmembrane mutation preventing ␥-chain association. In- of apoptotic Kupffer cells in their livers. Cuesta et al. (p. 3602) Ϫ/Ϫ teraction of Fc␣RI with the Src-family member Lyn was shown in the Vogel laboratory measured more apoptosis in IRF-2 by in vitro binding of Lyn to an Fc␣RI cytoplasmic tail frag- vs wild-type macrophages at the basal level and after exposure to ment, by anti-Lyn Ab recognition of Lyn in mouse cell proteins two different apoptosis inducers. Database analyses identified bound to affinity columns of anti-Fc␣RI mAb, and by anti- putative STAT binding sites within most of the shown by Fc␣RI Ab immunoblot detection of Fc␣RI in anti-Lyn Ab hybridization to DNA microarrays to be down-regulated pref- Ϫ/Ϫ immunoprecipitates from cell lysates. Lyn coimmunopre- erentially in livers of IRF-2 animals treated with LPS or sa- cipitated with the glycine, but not the serine, Fc␣RI mutant line. Protein and mRNA levels were lower for STAT3␤ but Ϫ/Ϫ containing the transmembrane mutation. Neutrophils from higher for STAT3␣ in IRF-2 macrophages with or without human donors homozygous for the glycine allele produced stimulation; mRNA for caspase-1 was up-regulated. However, more IL-6 after cross-linking with human IgA compared STAT3-, STAT1-, and p38 MAPK-activated phosphorylation Ϫ/Ϫ with those homozygous for the serine allele. The glycine al- levels were constitutively higher in unstimulated IRF-2 cells lele was found at higher frequency in African Americans and increased to a greater extent after stimulation than in wild- Downloaded from Ϫ/Ϫ compared with European-American controls and was en- type cells. Cell death was decreased in IRF-2 , but not wild- riched in patients from both groups with systemic lupus type, cells pretreated with a STAT3 inhibitory peptide, a erythematosus. The authors propose that the naturally oc- caspase-1 inhibitor, or a p38 MAPK inhibitor before apoptosis curring glycine allele of Fc␣RI increases receptor signaling induction. A novel IRF binding site in the promoter of the by direct interaction with Lyn and predisposes individuals to CASP1 was identified by computer analyses and shown by systemic lupus erythematosus. EMSA to bind to a nuclear complex containing IRF-1 plus http://www.jimmunol.org/ IRF-2 from stimulated or unstimulated wild-type cells; binding Ϫ Ϫ of the complex was enhanced in IRF-2 / cells. The data sug- Tether, Roll, Arrest gest that IRF-2 negatively regulates mouse macrophage apopto- sis via STAT1/STAT3 inhibition of caspase-1 expression. electins and integrins on circulating leuko- S cytes interact with STAT4 Is Pivotal in CIA their respective ligands on vas- by guest on September 24, 2021 lthough macrophage- cular endothelium to mediate derived cytokines are transmigration to inflamma- important in inflam- tory sites. To investigate the dependence of chemokine-trig- A matory synovitis in rheumatoid gered firm adhesion on VLA-4 integrin affinity or avidity, arthritis, there is evidence that in- DiVietro et al. (p. 3903) measured human peripheral blood filtrating T cells contribute to the leukocyte (PBL) adhesion to VCAM-1 in the presence or ab- disease. Hildner et al. (p. 3427) sence of stromal cell-derived factor-1␣ (SDF-1␣). Optimal looked at STAT4 activation in in- PBL tethering to VCAM-1 adsorbed to slides occurred at filtrating T cells in collagen-in- low density of ligand under low flow conditions; firm adhe- duced arthritis (CIA), the DBA/2 sion (arrest) was preferred over rolling at high-density mouse model for rheumatoid arthritis. Disease incidence, severity, and histopathology were nearly absent in collagen-immunized VCAM-1. Computer-assisted image processing techniques Ϫ Ϫ STAT4 / mice compared with wild-type controls. Ex vivo re- and high-speed video microscopy established at the millisec- Ϫ/Ϫ ond level that unstimulated PBL tethering to low site density stimulation of splenic T cells from immunized STAT4 animals showed diminished production of IFN-␥, IL-6, and TNF-␣. Al- VCAM-1 had a bimodal pattern with either transient or sta- though IFN-␥, but not IL-6 or TNF-␣, production from mutant ble interactions; coimmobilization of SDF-1␣ with cells was decreased at day 10 after immunization, collagen induced VCAM-1 significantly increased stable, and reduced tran- equal proliferation of mutant and wild-type T cells. STAT4 pro- sient, tethers. Interactions of PBL with VCAM-1 at high site tein had a bimodal increase in expression at 27 and 37 days postim- density were nearly twice as stable as interactions with munization in splenocytes from wild-type mice. Transfection with VCAM-1 at low site density. Coimmobilized SDF-1␣ in- STAT4 antisense oligonucleotides targeted to the translation start creased the low site density stable tethers and increased the site decreased STAT4 mRNA and protein as detected by RT-PCR number of arrested vs rolling PBLs; pertussis toxin blocked and EMSA, respectively. Collagen-immunized mice injected i.v. the SDF-1␣-induced increase. Titration of an anti-VLA-4 with the STAT4 antisense oligonucleotides on days 26 and 33 after ␣4 subunit mAb increased firm adhesion with VCAM-1 rel- CIA induction had significantly reduced incidence and severity of ative to rolling, whereas a small peptide that binds selectively arthritis compared with controls. The authors demonstrate the to high-affinity VLA-4 increased rolling over firmly adher- centrality of transcription factor STAT4 in CIA pathogenesis and ␥ ent interactions. The authors propose that SDF-1␣ induc- suggest that its primary influence is on IFN- production that tion of high-affinity VLA-4 is critical for arrest of tethered drives inflammation and recruitment of effector cells. PBL after a brief rolling interaction. Summaries written by Dorothy L. Buchhagen, Ph.D.