Browse Health
Dermatologist (skin)
11 years of experience
Accepting new patients
Video profile


Education ?

Medical School Score Rankings
Washington University at St. Louis (2001)
Internal Medicine
Top 25%

Awards & Distinctions ?

Patients' Choice Award (2010)
Compassionate Doctor Recognition (2010 - 2011)
Top 10 Doctor - City (2014)
Sarasota, FL
Florida State University
Assistant Professor
American Board of Dermatology

Affiliations ?

Dr. Long is affiliated with 2 hospitals.

Hospital Affiliations



  • Sarasota Memorial Hospital
    1700 S Tamiami Trl, Sarasota, FL 34239
    Top 25%
  • Doctors Hospital Of Sarasota
    5731 Bee Ridge Rd, Sarasota, FL 34233
    Top 50%
  • Publications & Research

    Dr. Long has contributed to 23 publications.
    Title Evaluation of the Ratio of Collagen Type Iii to Collagen Type I in Periurethral Tissues of Sexually Intact and Neutered Female Dogs.
    Date June 2010
    Journal American Journal of Veterinary Research

    To determine the ratio of collagen type III to collagen type I in the periurethral tissues of sexually intact and neutered female dogs.

    Title The Healthy Food Slide Rule (hfsr): a Nutrition Education Tool for Children.
    Date April 2010
    Journal Journal of Nutrition Education and Behavior
    Title Lipoteichoic Acid Induces Unique Inflammatory Responses when Compared to Other Toll-like Receptor 2 Ligands.
    Date August 2009
    Journal Plos One

    Toll-like receptors (TLRs) recognize evolutionarily-conserved molecular patterns originating from invading microbes. In this study, we were interested in determining if microbial ligands, which use distinct TLR2-containing receptor complexes, represent unique signals to the cell and can thereby stimulate unique cellular responses. Using the TLR2 ligands, R-FSL1, S-FSL1, Pam2CSK4, Pam3CSK4, and lipoteichoic acid (LTA), we demonstrate that these ligands activate NF-kappaB and MAP Kinase pathways with ligand-specific differential kinetics in murine macrophages. Most strikingly, LTA stimulation of these pathways was substantially delayed when compared with the other TLR2 ligands. These kinetics differences were associated with a delay in the LTA-induced expression of a subset of genes as compared with another TLR2 ligand, R-FSL1. However, this did not translate to overall differences in gene expression patterns four hours following stimulation with different TLR2 ligands. We extended this study to evaluate the in vivo responses to distinct TLR2 ligands using a murine model of acute inflammation, which employs intravital microscopy to monitor leukocyte recruitment into the cremaster muscle. We found that, although R-FSL1, S-FSL1, Pam2CSK4, and Pam3CSK4 were all able to stimulate robust leukocyte recruitment in vivo, LTA remained functionally inert in this in vivo model. Therefore distinct TLR2 ligands elicit unique cellular responses, as evidenced by differences in the kinetic profiles of signaling and gene expression responses in vitro, as well as the physiologically relevant differences in the in vivo responses to these ligands.

    Title Mice That Exclusively Express Tlr4 on Endothelial Cells Can Efficiently Clear a Lethal Systemic Gram-negative Bacterial Infection.
    Date July 2009
    Journal The Journal of Clinical Investigation

    Recognition of LPS by TLR4 on immune sentinel cells such as macrophages is thought to be key to the recruitment of neutrophils to sites of infection with Gram-negative bacteria. To explore whether endothelial TLR4 plays a role in this process, we engineered and imaged mice that expressed TLR4 exclusively on endothelium (known herein as EndotheliumTLR4 mice). Local administration of LPS into tissue induced comparable neutrophil recruitment in EndotheliumTLR4 and wild-type mice. Following systemic LPS or intraperitoneal E. coli administration, most neutrophils were sequestered in the lungs of wild-type mice and did not accumulate at primary sites of infection. In contrast, EndotheliumTLR4 mice showed reduced pulmonary capillary neutrophil sequestration over the first 24 hours; as a result, they mobilized neutrophils to primary sites of infection, cleared bacteria, and resisted a dose of E. coli that killed 50% of wild-type mice in the first 48 hours. In fact, the only defect we detected in EndotheliumTLR4 mice was a failure to accumulate neutrophils in the lungs following intratracheal administration of LPS; this response required TLR4 on bone marrow-derived immune cells. Therefore, endothelial TLR4 functions as the primary intravascular sentinel system for detection of bacteria, whereas bone marrow-derived immune cells are critical for pathogen detection at barrier sites. Nonendothelial TLR4 contributes to failure to accumulate neutrophils at primary infection sites in a disseminated systemic infection.

    Title The Phytochemical Piceatannol Induces the Loss of Cbl and Cbl-associated Proteins.
    Date June 2009
    Journal Molecular Cancer Therapeutics

    Piceatannol is a naturally occurring bioactive stilbene with documented antileukemic properties. It has been extensively used as a Syk-selective protein tyrosine kinase inhibitor for the study of various signaling pathways. Herein, we show that the hydroxystilbene, piceatannol, and related catechol ring-containing compounds are able to induce the loss of the Cbl family of proteins. Normal cellular Cbl-regulatory mechanisms were not involved in this process. Screening of a small library of piceatannol-like compounds indicated that aromaticity and a catechol ring were required for the induction of Cbl loss. Further examination of these two chemical properties showed that the oxidative conversion of the catechol ring of piceatannol into a highly reactive O-benzoquinone was the cause of piceatannol-induced Cbl loss. Characterization of the Cbl selectivity of piceatannol-induced protein loss revealed that this compound was also able to induce the functional loss of specific Cbl-associated proteins involved in signaling pathways commonly associated with cancer. This work uncovers a new, piceatannol-dependent effect and shows a novel way in which this phenomenon can be exploited to inhibit disease-associated signaling pathways.

    Title Eruptive Post-chemotherapy in Situ Melanomas and Dysplastic Nevi.
    Date July 2007
    Journal Pediatric Dermatology

    A 22-year-old white man without a personal or family history of atypical nevi had received chemotherapy for pre-B-cell acute lymphocytic leukemia at age 17 that included L-asparaginase, prednisone, methotrexate, mercaptopurine, daunorubicin, and cytoxan. Two to three months after completing maintenance chemotherapy, the patient reports he developed many moles, which remained stable for approximately 2 years. Upon examination, two dark, atypical appearing plaques with irregular borders and numerous pink papules of varying shapes and sizes were noted on his chest, back, and abdomen. Histology of specimens of both types of lesions revealed three moderately atypical compound dysplastic melanocytic nevi and three in situ melanomas. The lesions with only features of dysplastic nevi exhibited dermal fibrosis, cytologic atypia, junctional shoulders, lentiginous spread, and focal pigmentation. The lesions with in situ melanomas in addition demonstrated pagetoid spread, extension down adnexal structures, and more severe cytologic atypia. Malignant melanoma has been associated with chronic immunosuppression, and benign nevi have been reported to erupt after chemotherapy. We report an occurrence of multiple eruptive dysplastic nevi and in situ melanomas appearing shortly after completion of chemotherapy.

    Title The Birc1e Cytosolic Pattern-recognition Receptor Contributes to the Detection and Control of Legionella Pneumophila Infection.
    Date April 2006
    Journal Nature Immunology

    Baculovirus inhibitor of apoptosis repeat-containing 1 (Birc1) proteins have homology to several germline-encoded receptors of the innate immune system. However, their function in immune surveillance is not clear. Here we describe a Birc1e-dependent signaling pathway that restricted replication of the intracellular pathogen Legionella pneumophila in mouse macrophages. Translocation of bacterial products into host-cell cytosol was essential for Birc1e-mediated control of bacterial replication. Caspase-1 was required for Birc1e-dependent antibacterial responses ex vivo in macrophages and in a mouse model of Legionnaires' disease. The interleukin 1beta converting enzyme-protease-activating factor was necessary for L. pneumophila growth restriction, but interleukin 1beta was not required. These results establish Birc1e as a nucleotide-binding oligomerization-leucine-rich repeat protein involved in the detection and control of intracellular L. pneumophila.

    Title Immune Cell Toll-like Receptor 4 is Required for Cardiac Myocyte Impairment During Endotoxemia.
    Date April 2005
    Journal Circulation Research

    The aim of this study was to investigate the importance of Toll-like receptor 4 (TLR4) signaling on cardiac myocytes versus immune cells in lipopolysaccharide (LPS)-induced cardiac dysfunction. Cardiac myocytes isolated from LPS-treated C57Bl/6 mice showed reduced shortening and calcium transients as compared with myocytes from untreated mice. In addition, LPS-treated C57Bl/6 mice showed impaired cardiac mitochondrial function, including reduced respiration and reduced time of induction of permeability transition. All of the aforementioned cardiac dysfunction was dependent on TLR4, because LPS-treated TLR4-deficient mice did not have reduced myocyte shortening or mitochondrial dysfunction. To evaluate the role of cardiac myocyte versus leukocyte TLR4, LPS was injected into chimeric mice with TLR4-positive leukocytes and TLR4-deficient myocytes. These mice showed reduced myocyte shortening in response to LPS. Myocytes from chimeric mice with TLR4-deficient leukocytes and TLR4-positive myocytes had no response to LPS. In addition, isolated myocytes from C57Bl/6 mice subsequently treated with LPS and serum for various times did not have reduced shortening, despite the presence of TLR4 mRNA and protein, as determined by reverse-transcription polymerase chain reaction and fluorescent-activated cell sorting. In fact, cardiac myocytes had equivalent amounts of TLR4 as endothelium; however, only the latter is responsive to LPS. Furthermore, signaling pathways downstream of TLR4 were not activated during direct LPS treatment of myocytes. In conclusion, TLR4 on leukocytes, and not on cardiac myocytes, is important for cardiac myocyte impairment during endotoxemia.

    Title Tlr4 Contributes to Disease-inducing Mechanisms Resulting in Central Nervous System Autoimmune Disease.
    Date January 2005
    Journal Journal of Immunology (baltimore, Md. : 1950)

    Environmental factors strongly influence the development of autoimmune diseases, including multiple sclerosis. Despite this clear association, the mechanisms through which environment mediates its effects on disease are poorly understood. Pertussis toxin (PTX) functions as a surrogate for environmental factors to induce animal models of autoimmunity, such as experimental autoimmune encephalomyelitis. Although very little is known about the molecular mechanisms behind its function in disease development, PTX has been hypothesized to facilitate immune cell entry to the CNS by increasing permeability across the blood-brain barrier. Using intravital microscopy of the murine cerebromicrovasculature, we demonstrate that PTX alone induces the recruitment of leukocytes and of active T cells to the CNS. P-selectin expression was induced by PTX, and leukocyte/endothelial interactions could be blocked with a P-selectin-blocking Ab. P-selectin blockade also prevented PTX-induced increase in permeability across the blood-brain barrier. Therefore, permeability is a secondary result of recruitment, rather than the primary mechanism by which PTX induces disease. Most importantly, we show that PTX induces intracellular signals through TLR4, a receptor intimately associated with innate immune mechanisms. We demonstrate that PTX-induced leukocyte recruitment is dependent on TLR4 and give evidence that the disease-inducing mechanisms initiated by PTX are also at least partly dependent on TLR4. We propose that this innate immune pathway is a novel mechanism through which environment can initiate autoimmune disease of the CNS.

    Title Human Immunodeficiency Virus Type 1 (hiv-1) Diversity at Time of Infection is Not Restricted to Certain Risk Groups or Specific Hiv-1 Subtypes.
    Date July 2004
    Journal Journal of Virology

    African women frequently acquire several genetically distinct human immunodeficiency virus type 1 (HIV-1) variants from a heterosexual partner, whereas the acquisition of multiple variants appears to be rare in men. To determine whether newly infected individuals in other risk groups acquire genetically diverse viruses, we examined the viral envelope sequences in plasma samples from 13 women and 4 men from the United States infected with subtype B viruses and 10 men from Kenya infected with non-subtype B viruses. HIV-1 envelope sequences differed by more than 2% in three U.S. women, one U.S. man, and one Kenyan man near the time of seroconversion. These findings suggest that early HIV-1 genetic diversity is not exclusive to women from Africa or to infection with any particular HIV-1 subtype.

    Title Stimulation of the Murine Uchl1 Gene Promoter by the B-myb Transcription Factor.
    Date February 2004
    Journal Lung Cancer (amsterdam, Netherlands)

    It has been reported that human lung cancers frequently overexpress both the ubiquitous cell cycle transcription factor B-myb and the ubiquitin carboxyterminal hydrolase UCHL1, an enzyme whose expression is normally limited to neurons and neuroendocrine cells in the lung. A possible explanation for the co-expression of these markers is that Uchl1 is subject to transcriptional regulation by B-Myb, and in tumors the ectopic expression of UCHL1 is a direct consequence of B-Myb overexpression. We have tested this hypothesis in the mouse model system by cloning the murine Uchl1 promoter and analyzing its regulation by murine B-Myb. Expression of a luciferase reporter gene driven by the Uchl1 promoter was induced by cotransfected B-Myb, but induction was not dependent on the presence of a myb consensus binding site identified in the promoter region. B-Myb induction was dependent on the context of the Uchl1 TATA box, as has been reported for other genes. Transgenic mice expressing a truncated, constitutively active form of B-Myb in the lung epithelium showed elevated expression of UCHL1 protein. We conclude that B-Myb can stimulate expression of the Uchl1 both in cultured cells and in vivo.

    Title Naip5 Affects Host Susceptibility to the Intracellular Pathogen Legionella Pneumophila.
    Date September 2003
    Journal Current Biology : Cb

    BACKGROUND: Legionella pneumophila is a gram-negative bacterial pathogen that is the cause of Legionnaires' Disease. Legionella produces disease because it can replicate inside a specialized compartment of host macrophages. Macrophages isolated from various inbred mice exhibit large differences in permissiveness for intracellular replication of Legionella. A locus affecting this host-resistance phenotype, Lgn1, has been mapped to chromosome 13, but the responsible gene has not been identified. RESULTS: Here, we report that Naip5 (also known as Birc1e) influences susceptibility to Legionella. Naip5 encodes a protein that is homologous to plant innate immunity (so-called "resistance") proteins and has been implicated in signaling pathways related to apoptosis regulation. Detailed recombination mapping and analysis of expression implicates Naip5 in the Legionella permissiveness differences among mouse strains. A bacterial artificial chromosome (BAC) transgenic line expressing a nonpermissive allele of Naip5 exhibits a reduction in macrophage Legionella permissiveness. In addition, morpholino-based antisense inhibition of Naip5 causes an increase in the Legionella permissiveness of macrophages. CONCLUSIONS: We conclude that polymorphisms in Naip5 are involved in the permissiveness differences of mouse macrophages for intracellular Legionella replication. We speculate that Naip5 is a functional mammalian homolog of plant "resistance" proteins that monitor for, and initiate host response to, the presence of secreted bacterial virulence proteins.

    Title Hiv Type 1 Variants Transmitted to Women in Kenya Require the Ccr5 Coreceptor for Entry, Regardless of the Genetic Complexity of the Infecting Virus.
    Date July 2002
    Journal Aids Research and Human Retroviruses

    Although nearly half of the HIV-1-infected adults in the world are women, little is known about the virologic determinants of transmission to women. Studies suggest that women are frequently infected with multiple HIV-1 genotypes, whereas men are infected with a single genotype. In the current study, we assessed whether the diverse HIV-1 genomes present at the time of infection in women encode viruses that have diverse coreceptor specificities. For this purpose, we defined the coreceptor requirements of viruses found in recently infected Kenyan women, three of whom had multiple viral genotypes and the remaining two of whom had a single genotype. Full-length envelope clones were amplified directly from blood and the dominant genotypes were identified. Envelope clones derived from all five women were able to pseudotype infectious particles competent to infect cells expressing CCR5, but not cells expressing only CXCR4. Thus, regardless of viral complexity at the time of infection, the viruses present at early stages of HIV-1 infection in women use CCR5, suggesting that cells expressing CCR5 are important targets for heterosexual HIV-1 transmission to women.

    Title Gender Differences in Hiv-1 Diversity at Time of Infection.
    Date February 2000
    Journal Nature Medicine

    To develop an HIV-1 vaccine with global efficacy, it is important to identify and characterize the viruses that are transmitted, particularly to individuals living in areas of high incidence. Several studies have shown that virus from the blood of acutely infected adults was homogeneous, even when the virus population in the index case was genetically diverse. In contrast to those results with mainly male cohorts in America and Europe, in several cases a heterogeneous virus population has been found early in infection in women in Africa. Thus, we more closely compared the diversity of transmitted HIV-1 in men and women who became infected through heterosexual contact. We found that women from Kenya were often infected by multiple virus variants, whereas men from Kenya were not. Moreover, a heterogeneous virus was present in the women before their seroconversion, and in each woman it was derived from a single index case, indicating that diversity was most likely to be the result of transmission of multiple variants. Our data indicate that there are important differences in the transmitted virus populations in women and men, even when cohorts from the same geographic region who are infected with the same subtypes of HIV-1 are compared.

    Title Studies of Human Immunodeficiency Virus Type 1 Mucosal Viral Shedding and Transmission in Kenya.
    Date May 1999
    Journal The Journal of Infectious Diseases

    If human immunodeficiency virus type 1 (HIV-1) vaccines are to be highly effective, it is essential to understand the virologic factors that contribute to HIV-1 transmission. It is likely that transmission is determined, in part, by the genotype or phenotype (or both) of infectious virus present in the index case, which in turn will influence the quantity of virus that may be exchanged during sexual contact. Transmission may also depend on the fitness of the virus for replication in the exposed individual, which may be influenced by whether a virus encounters a target cell that is susceptible to infection by that specific variant. Of interest, our data suggest that the complexity of the virus that is transmitted may be different in female and male sexual exposures.

    Title Four-week Supplementation with a Natural Dietary Compound Produces Favorable Changes in Body Composition.
    Date March 1999
    Journal Advances in Therapy

    The purpose of this study was to determine whether a natural dietary supplement produced favorable changes in body composition during a 4-week diet- and-exercise program. The active compound contains a patented combination of chromium picolinate, inulin, capsicum, L-phenylalanine, and other lipotropic nutrients. A double-blind, weight-loss intervention design was used. Participants were randomly assigned to either a diet/exercise/supplement group (n = 56) or a diet/exercise/placebo group (n = 67). Caloric intake was reduced to 1500 kcal/d and participants walked for 45 minutes, 5 days a week, to attain between 60% and 80% of predicted maximal heart rate. Analysis of covariance (ANCOVA) showed significant differences (P < .05) between groups in percent body fat, fat mass, and fat-free mass; no significant differences were found (P > .05) in body weight, body mass index, or energy intake. Independent t tests showed no significant differences (P > .05) in diet composition between groups. Results indicate that the addition of a natural dietary supplement during a 4-week diet-and-exercise weight-loss program accelerates the rate of body fat loss and helps maintain fat-free mass (lean tissue), thereby producing favorable changes in body composition.

    Title Changes in the Extracellular Envelope Glycoprotein of Variants That Evolve During the Course of Simian Immunodeficiency Virus Sivmne Infection Affect Neutralizing Antibody Recognition, Syncytium Formation, and Macrophage Tropism but Not Replication, Cytopathicity, or Ccr-5 Coreceptor Recognition.
    Date January 1998
    Journal Journal of Virology

    Simian immunodeficiency virus SIVMne, like human immunodeficiency virus, evolves from a macrophage-tropic, non-syncytium-inducing virus at early times in infection to a T-cell-tropic, syncytium-inducing, cytopathic virus population over the course of progression to AIDS. Because the viruses isolated late in SIVMne infection of macaques include a complex mixture of variants, the viral determinants of such phenotypic changes have not been defined. To identify genetic changes that are important to virus evolution in the host, we constructed chimeric viruses by introducing variant envelope genes representative of proviruses throughout the course of infection and disease into the SIVMne parental clone (SIVMneCL8) that infected the macaque. The chimeric viruses expressed sequences encoding the surface unit of the envelope glycoprotein (Env-SU) of variants cloned between 35 and 170 weeks postinfection. The chimera with Env-SU from 35 weeks postinfection encoded only four changes in V1 compared to SIVMneCL8, whereas the chimeras encoding Env-SU from variants isolated later in infection encoded progressively more mutations both in V1 and elsewhere. Like SIVMneCL8, the chimeras were infectious for CEMx174 cells and macaque peripheral blood mononuclear cells. However, in contrast to SIVMneCL8, the chimeric viruses did not infect macaque macrophages, although each retained the ability to recognize the CCR-5 coreceptor. Thus, these data provide direct evidence that changes which evolve in Env-SU during the course of SIVMne infection do not alter CCR-5 interactions. Viruses encoding Env-SU from the latest times in infection (121 to 170 weeks postinfection), after disease was apparent, were syncytium inducing. However, these viruses were not highly cytopathic, suggesting that additional viral determinants may be required for the rapidly replicating, cytopathic phenotype of the uncloned mixed variant population. Changes in Env-SU did allow the virus to escape serum neutralizing antibodies that recognized the SIVMneCL8 parent. Moreover, the chimera encoding the Env-SU of a virus from 35 weeks postinfection, which differed from SIVMneCL8 only in V1, was not sensitive to neutralization by infected macaque sera, suggesting that V1 may define a portion of the principal neutralizing determinant for SIVMne. Together, these data suggest that SIV variants with changes in the Env-SU may be selected primarily by virtue of their ability to escape neutralizing antibody recognition.

    Title Human Immunodeficiency Virus Type 1 Coreceptors Participate in Postentry Stages in the Virus Replication Cycle and Function in Simian Immunodeficiency Virus Infection.
    Date April 1997
    Journal Journal of Virology

    Primate lentiviruses use chemokine coreceptors in addition to the CD4 receptor to initiate virus infection. Simian immunodeficiency virus (SIV) productively infects human cells expressing CD4 and the human allele of the chemokine coreceptor CCR-5 as efficiently as it infects macaque cells expressing human CD4, suggesting that SIV can function with either a simian or a human coreceptor in conjunction with human CD4. In the same macaque cells expressing human CD4, the replication of human immunodeficiency virus type 1 (HIV-1) is blocked at several stages of infection; some isolates are restricted prior to reverse transcription, while others, including some macrophage-tropic and primary isolates, are restricted at a step after reverse transcription but prior to migration of the preintegration complex to the nucleus. Both blocks in HIV-1 replication can be relieved by either expression of the appropriate human coreceptor (CCR-5 or CXCR-4) or expression of SIV gene products in cis with the HIV-1 envelope as a chimera between SIV and HIV-1 (SHIV). Thus, a virus with a SIV core and HIV-1 envelope can efficiently infect macaque cells expressing human CD4, presumably by interacting with the simian coreceptor, whereas a virus with an HIV-1 core and an HIV-1 envelope requires expression of the human allele of the coreceptor for productive infection of these cells. These studies suggest that there are interactions among the coreceptor, the viral envelope, and another viral gene product that govern postentry steps of virus replication. These data are consistent with the hypothesis that such interactions may be required for translocation of the virus core to the nucleus. Moreover, the differential abilities of SIV and HIV-1 to function in these processes with heterologous primate coreceptors may have implications for cross-species transmission.

    Title Factors Related to Low Milk Intake of 3- to 5-year-old Children in Child Care Settings.
    Date October 1996
    Journal Journal of the American Dietetic Association
    Title Nutrition Education Sources and Priorities of Elementary School Teachers.
    Date April 1994
    Journal Journal of the American Dietetic Association
    Title Outcome of Fetal Meningomyelocele After Vaginal Delivery.
    Date November 1987
    Journal The Journal of Reproductive Medicine

    Eight neonates with meningomyelocele were delivered vaginally. Diagnosis of meningomyelocele was made by ultrasonography during the latter half of pregnancy in three patients. The remaining five did not have ultrasound examination during the antenatal period. None of the meningomyelocele sacs (less than or equal to 4 cm in diameter) was ruptured at the time of delivery. Cesarean section may not be necessary for all fetuses with meningomyelocele.

    Title Ectopic Pregnancy. An Eight-year Review.
    Date July 1979
    Journal The Journal of Reproductive Medicine

    Ruptured ectopic pregnancy constitutes a major gynecologic emergency that may result in death. From January 1968 through December 1975, 313 patients with ectopic pregnancy were treated at Chicago Lying-In Hospital. The historical and physical findings, diagnostic procedures, causative factors and patient management are reviewed and discussed. The most common symptoms were abdominal pain and amenorrhea. More than half the patients were misdiagnosed prior to admission. Only 30% had distinct adnexal masses. The treatment of choice was salpingectomy unless the opposite tube was absent or damaged. Three deaths occurred in this series. Only 31% of the patients gave histopathologic evidence of pelvic inflammatory disease.

    Title Endothelial Lsp1 is Involved in Endothelial Dome Formation, Minimizing Vascular Permeability Changes During Neutrophil Transmigration in Vivo.
    Journal Blood

    The endothelium actively participates in neutrophil migration out of the vasculature via dynamic, cytoskeleton-dependent rearrangements leading to the formation of transmigratory cups in vitro, and to domes that completely surround the leukocyte in vivo. Leukocyte-specific protein 1 (LSP1), an F-actin-binding protein recently shown to be in the endothelium, is critical for effective transmigration, although the mechanism has remained elusive. Herein we show that endothelial LSP1 is expressed in the nucleus and cytosol of resting endothelial cells and associates with the cytoskeleton upon endothelial activation. Two-photon microscopy revealed that endothelial LSP1 was crucial for the formation of endothelial domes in vivo in response to neutrophil chemokine keratinocyte-derived chemokine (KC) as well as in response to endogenously produced chemokines stimulated by cytokines (tumor necrosis factor α [TNFα] or interleukin-1β [IL-1β]). Endothelial domes were significantly reduced in Lsp1(-/-) compared with wild-type (WT) mice. Lsp1(-/-) animals not only showed impaired neutrophil emigration after KC and TNFα stimulation, but also had disproportionate increases in vascular permeability. We demonstrate that endothelial LSP1 is recruited to the cytoskeleton in inflammation and plays an important role in forming endothelial domes thereby regulating neutrophil transendothelial migration. The permeability data may underscore the physiologic relevance of domes and the role for LSP1 in endothelial barrier integrity.

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