The Chemokine Receptor CXCR2 Ligand KC (CXCL1) Mediates Neutrophil Recruitment and Is Critical for Development of Experimental Lyme Arthritis and Carditis

Ritzman, Anna M.; Hughes-Hanks, Jennifer M.; Blaho, Victoria A.; Wax, Laura E.; Mitchell, William J.; Brown, Charles R.

doi:10.1128/iai.00798-10

Cited by 106 publications

(107 citation statements)

References 56 publications

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“…IL-6, CXCL1 (KC), CXCL2 (MIP-2), CXCL9 (MIG), CXCL10 (IP-10), CCL2 (MCP-1), CCL3/4 (MIP-1␣/␤), and CCL5 (RANTES) cytokines/chemokines are essential for recruitment of several cell types (20,26). The proinflammatory cytokine IL-6 and the chemokines CXCL1 and CXCL2, which mainly induce neutrophil migration (27,28), were significantly overexpressed in PEs of NYVAC-C Δ3-injected mice compared to those of mice injected with the other deletion mutants (Fig. 3A to C).…”

Section: Resultsmentioning

confidence: 99%

Distinct Roles of Vaccinia Virus NF-κB Inhibitor Proteins A52, B15, and K7 in the Immune Response

Pilato

Mejías-Pérez

Sorzano

et al. 2017

J Virol

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Poxviruses use a complex strategy to escape immune control, by expressing immunomodulatory proteins that could limit their use as vaccine vectors. To test the role of poxvirus NF-B pathway inhibitors A52, B15, and K7 in immunity, we deleted their genes in an NYVAC (New York vaccinia virus) strain that expresses HIV-1 clade C antigens. After infection of mice, ablation of the A52R, B15R, and K7R genes increased dendritic cell, natural killer cell, and neutrophil migration as well as chemokine/cytokine expression. Revertant viruses with these genes confirmed their role in inhibiting the innate immune system. To different extents, enhanced innate immune responses correlated with increased HIV Pol-and Gag-specific polyfunctional CD8 T cell and HIV Env-specific IgG responses induced by single-, double-, and triple-deletion mutants. These poxvirus proteins thus influence innate and adaptive cell-mediated and humoral immunity, and their ablation offers alternatives for design of vaccine vectors that regulate immune responses distinctly.IMPORTANCE Poxvirus vectors are used in clinical trials as candidate vaccines for several pathogens, yet how these vectors influence the immune system is unknown. We developed distinct poxvirus vectors that express heterologous antigens but lack different inhibitors of the central host-cell signaling pathway. Using mice, we studied the capacity of these viruses to induce innate and adaptive immune responses and showed that these vectors can distinctly regulate the magnitude and quality of these responses. These findings provide important insights into the mechanism of poxvirus-induced immune response and alternative strategies for vaccine vector design.KEYWORDS NF-B, NYVAC, T cell immunity, adaptive immunity, human immunodeficiency virus, immunomodulation, innate immunity, poxvirus, vaccines, vaccinia virus S everal vaccine strategies have been developed to improve immune responses to heterologous antigens expressed by attenuated poxvirus vectors (1). Given the limited effectiveness of the ALVAC poxvirus vector in the RV144 phase III HIV/AIDS clinical trial (2), the need remains to improve poxvirus vector capacity as an immunogen, to increase protection levels, and to understand how innate and adaptive immune responses can be regulated.The attenuated poxvirus strain NYVAC (New York vaccinia virus) has been used as a vaccine vector in HIV clinical trials (3,4). Studies in nonhuman primates showed that NYVAC expressing Env and/or the Gag-Pol-Nef (GPN) clade C HIV antigens elicited a balanced CD4/CD8 T cell response (5) or robust T cell immunity (6). In clinical trials in healthy volunteers and in chronically HIV-infected patients, NYVAC showed clear immunogenic potential to induce expansion of preexisting T cell responses as well as the appearance of newly detected polyfunctional CD8 T cell responses (7).

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Section: Resultsmentioning

confidence: 99%

Distinct Roles of Vaccinia Virus NF-κB Inhibitor Proteins A52, B15, and K7 in the Immune Response

Pilato

Mejías-Pérez

Sorzano

et al. 2017

J Virol

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“…Increased levels of neutrophil-and macrophage/monocyteattracting chemokines in the CRB and BS in LysMCre-SOCS3 fl//fl mice with atypical EAE CXCL1, CXCL2, and CCL2 are potent neutrophil and macrophage chemoattractants (8,37,38). Given the increased levels of neutrophils and macrophages/monocytes infiltrating into the CRB and BS in LysMCre-SOCS3 fl//fl mice with atypical EAE compared with SOCS3…”

Section: Neutrophil Infiltration Into the Crb And Bs Is Prominent Inmentioning

confidence: 99%

Preferential Recruitment of Neutrophils into the Cerebellum and Brainstem Contributes to the Atypical Experimental Autoimmune Encephalomyelitis Phenotype

Liu

Holdbrooks

Meares

et al. 2015

The Journal of Immunology

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The JAK/STAT pathway is critical for development, regulation, and termination of immune responses, and dysregulation of the JAK/STAT pathway, that is, hyperactivation, has pathological implications in autoimmune and neuroinflammatory diseases. Suppressor of cytokine signaling 3 (SOCS3) regulates STAT3 activation in response to cytokines that play important roles in the pathogenesis of neuroinflammatory diseases, including IL-6 and IL-23. We previously demonstrated that myeloid lineage-specific deletion of SOCS3 resulted in a severe, nonresolving atypical form of experimental autoimmune encephalomyelitis (EAE), characterized by lesions, inflammatory infiltrates, elevated STAT activation, and elevated cytokine and chemokine expression in the cerebellum. Clinically, these mice exhibit ataxia and tremors. In this study, we provide a detailed analysis of this model, demonstrating that the atypical EAE observed in LysMCre-SOCS3 fl/fl mice is characterized by extensive neutrophil infiltration into the cerebellum and brainstem, increased inducible NO synthase levels in the cerebellum and brainstem, and prominent axonal damage. Importantly, infiltrating SOCS3-deficient neutrophils produce high levels of CXCL2, CCL2, CXCL10, NO, TNF-a, and IL-1b. Kinetic studies demonstrate that neutrophil infiltration into the cerebellum and brainstem of LysMCre-SOCS3 fl/fl mice closely correlates with atypical EAE clinical symptoms. Ab-mediated depletion of neutrophils converts the atypical phenotype to the classical EAE phenotype and, in some cases, a mixed atypical/classical phenotype. Blocking CXCR2 signaling ameliorates atypical EAE development by reducing neutrophil infiltration into the cerebellum/brainstem. Thus, neutrophils lacking SOCS3 display elevated STAT3 activation and expression of proinflammatory mediators and play a critical role in the development of atypical EAE.

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“…For example, the 2 commonly studied CXCR2 chemokine ligands in the mouse, CXCL1 (Gro alpha, KC), and CXCL2 (Gro beta, MIP-2) were shown to have differing affinities for the CXCR2 receptor, resulting in a hierarchy of neutrophil chemotaxis and activation (Lee et al 1995;Wuyts et al 1996). Furthermore, the kinetics of expression and tissue expression profiles in several different models of infection revealed that these CXCR2 ligands display both differences in temporal and spatial responses, suggesting differing functional roles for these ligands in different disease models (Rovai et al 1998;Ritzman et al 2010;Mei et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Site-Specific Neutrophil Migration and CXCL2 Expression in Periodontal Tissue

et al. 2016

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The oral microbial community is the best-characterized bacterial ecosystem in the human host. It has been shown in the mouse that oral commensal bacteria significantly contribute to clinically healthy periodontal homeostasis by influencing the number of neutrophils that migrate from the vasculature to the junctional epithelium. Furthermore, in clinically healthy tissue, the neutrophil response to oral commensal bacteria is associated with the select expression of the neutrophil chemokine CXCL2 but not CXCL1. This preliminary study examined the contribution of commensal bacteria on neutrophil location across the tooth/gingival interface. Tissue sections from the root associated mesial (anterior) of the second molar to the root associated distal (posterior) of the second molar were examined for neutrophils and the expression of the neutrophil chemokine ligands CXCL1 and CXCL2. It was found that both the number of neutrophils as well as the expression of CXCL2 but not CXCL1 was significantly increased in tissue sections close to the interdental region, consistent with the notion of select tissue expression patterns for neutrophil chemokine expression and subsequent neutrophil location. Furthermore, mice gavaged with either oral Streptococcus or Lactobacillus sp. bacteria induced a location pattern of neutrophils and CXCL2 expression similar to the normal oral flora. These data indicate for the first time select neutrophil location and chemokine expression patterns associated with clinically healthy tissue. The results reveal an increased inflammatory load upon approaching the interproximal region, which is consistent with the observation that the interproximal region often reveals early clinical signs of periodontal disease.

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The Chemokine Receptor CXCR2 Ligand KC (CXCL1) Mediates Neutrophil Recruitment and Is Critical for Development of Experimental Lyme Arthritis and Carditis

Cited by 106 publications

References 56 publications

Distinct Roles of Vaccinia Virus NF-κB Inhibitor Proteins A52, B15, and K7 in the Immune Response

Distinct Roles of Vaccinia Virus NF-κB Inhibitor Proteins A52, B15, and K7 in the Immune Response

Preferential Recruitment of Neutrophils into the Cerebellum and Brainstem Contributes to the Atypical Experimental Autoimmune Encephalomyelitis Phenotype

Site-Specific Neutrophil Migration and CXCL2 Expression in Periodontal Tissue

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