Tpl2 promotes neutrophil trafficking, oxidative burst, and bacterial killing

Acuff, Nicole; Li, Xin; Elmore, Jessica; Rada, Balázs; Watford, Wendy T.

doi:10.1189/jlb.3a0316-146r

Cited by 16 publications

(13 citation statements)

References 61 publications

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“…These results are consistent with the finding that Tpl2 regulates the expression of inflammatory cytokines and chemokines and the recruitment of neutrophils to sites of inflammation (52)(53)(54)(55)65). The reduced intestinal pathology in Tpl2 Ϫ/Ϫ mice may also be due to greater dissemination, which would induce a more diffuse and less localized inflammatory response in the host.…”

Section: Figsupporting

confidence: 81%

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Tpl2 Promotes Innate Cell Recruitment and Effector T Cell Differentiation To Limit Citrobacter rodentium Burden and Dissemination

Acuff

Latha

et al. 2017

Infect Immun

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Tumor progression locus 2 (Tpl2) is a serine-threonine kinase that regulates Th1 differentiation, secretion of the inflammatory cytokine gamma interferon (IFN-␥), and host defense against the intracellular pathogens Toxoplasma gondii, Listeria monocytogenes, and Mycobacterium tuberculosis. However, relatively little is known about the contribution of Tpl2 to Th17 differentiation and immune cell function during infection with an extracellular pathogen. The goal of this study was to determine whether Tpl2 influences the immune response generated to the extracellular bacterium Citrobacter rodentium, which induces a mixed Th1 and Th17 response. During peak infection with C. rodentium, Tpl2 Ϫ/Ϫ mice experienced greater bacterial burdens with evidence of dissemination to the liver and spleen but ultimately cleared the bacteria within 3 weeks postinfection, similar to the findings for wild-type mice. Tpl2 Ϫ/Ϫ mice also recruited fewer neutrophils and monocytes to the colon during peak infection, which correlated with increased bacterial burdens. In mixed bone marrow chimeras, Tpl2 was shown to play a T cell-intrinsic role in promoting both IFN-␥ and interleukin-17A production during infection with C. rodentium. However, upon CD4 T cell transfer into Rag Ϫ/Ϫ mice, Tpl2 Ϫ/Ϫ CD4 T cells were as protective as wild-type CD4 T cells against the dissemination of bacteria and mortality. These data indicate that the enhanced bacterial burdens in Tpl2 Ϫ/Ϫ mice are not caused primarily by impairments in CD4 T cell function but result from defects in innate immune cell recruitment and function. KEYWORDS Citrobacter, T helper cells, gastrointestinal infection, intestinal immunity, neutrophilsC itrobacter rodentium is a nonmotile Gram-negative rod that is a natural mouse and gerbil pathogen (1, 2). Upon infection, C. rodentium colonizes the large intestine, primarily the cecum and distal portion of the colon (3), and forms a close association with the epithelium and lamina propria that results in attaching and effacing lesions in the large intestine (4, 5). However, C. rodentium can disseminate out of the intestines and be found in the nasopharynx, lung, heart, liver, and spleen (6). Early innate responses to C. rodentium are associated with recruitment and the antimicrobial functions of neutrophils, macrophages, NK cells, and innate lymphoid cells (7-12). Neutrophils secrete interleukin-17A (IL-17A) and IL-22, promote the production of antimicrobial defensins by epithelial cells, and protect against the development of diarrhea (11,13). The bacterial association with the lamina propria of the large intestine subsequently induces a mixed Th1 and Th17 response associated with IL-12, gamma interferon (IFN-␥), tumor necrosis factor (TNF), . Clearance of the bacteria occurs within 3 weeks in a wild-type host and is dependent upon both CD4 T cell and B cell functions (18, 19).Tumor progression locus 2 (Tpl2; also known as MAP3K8) is a serine-threonine Citation Acuff NV, Li X, Latha K, Nagy T, Watford WT. 2017. Tpl2 promotes innat...

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Section: Figsupporting

confidence: 81%

“…6C). The reduced levels of neutrophil recruitment in Tpl2 Ϫ/Ϫ mice are consistent with previous reports of impaired neutrophil recruitment in models of inflammation primarily due to factors extrinsic to neutrophils (52)(53)(54)(55).…”

Section: Figsupporting

confidence: 81%

Tpl2 Promotes Innate Cell Recruitment and Effector T Cell Differentiation To Limit Citrobacter rodentium Burden and Dissemination

Acuff

Latha

et al. 2017

Infect Immun

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“…Therefore, it is not surprising we found in the present study that Tpl2 functioned in hepatocyte to modulate Cxcl1/2 expression, which then modulated the recruitment of MDSC into liver during FH pathogenesis. A recent study has suggested that Tpl2 exhibited neutrophil intrinsic function to mediate the trafficking of this type of immune cells (37), so it is also possible that Tpl2 may functioned directly in MDSC to promote its liver mobilization in FH mice. However, the increased mortality was only observed in Tpl2 germline knockout FH mice or Tpl2 -deficient recipient chimeric FH mice that adoptively transferred with WT BM, but not in the WT recipient chimeric FH mice that adoptively transferred with either WT or Tpl2 -deficient BM, suggesting the liver MDSC mobilization during FH pathogenesis is not attributed to the direct intrinsic function of Tpl2 in MDSC, but in hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Tpl2 Protects Against Fulminant Hepatitis Through Mobilization of Myeloid-Derived Suppressor Cells

Pei

Wang

et al. 2019

Front. Immunol.

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Myeloid derived suppressor cells (MDSC) in the liver microenvironment protects against the inflammation-induced liver injury in fulminant hepatitis (FH). However, the molecular mechanism through which MDSC is recruited into the inflamed liver remain elusive. Here we identified a protein kinase Tpl2 as a critical mediator of MDSC recruitment into liver during the pathogenesis of Propionibacterium acnes /LPS-induced FH. Loss of Tpl2 dramatically suppressed MDSC mobilization into liver, leading to exaggerated local inflammation and increased FH-induced mortality. Mechanistically, although the protective effect of Tpl2 for FH-induced mortality was dependent on the presence of MDSC, Tpl2 neither directly targeted myeloid cells nor T cells to regulate FH pathogenesis, but functioned in hepatocytes to mediate the induction of MDSC-attracting chemokine CXCL1 and CXCL2 through modulating IL-25 (also known as IL-17E) signaling. As a consequence, increased MDSC in the inflamed liver specifically restrained the local proliferation of infiltrated pathogenic CD4 + T cells, and thus protected against the inflammation-induced acute liver failure. Together, our findings established Tpl2 as a critical mediator of MDSC recruitment and highlighted the therapeutic potential of Tpl2 for the treatment of FH.

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“…In-line with this, patients suffering from systemic sclerosis and cerebrovascular inflammation show clear signs of localized hypoxia, and fibroblasts from these patients show marked increases in activation of p38 [85–87]. In addition, MAP3K8 −/− mice have reduced amounts of circulating neutrophils, which display impaired sensitivity to chemokines and lower TNF-α secretion [57,58]. Bone-marrow derived DCs of MAP3K8 −/− mice also show impaired TNF-α secretion [88] and increased IL-12 [89].…”

Section: Discussionmentioning

confidence: 97%

Hypoxia potentiates monocyte-derived dendritic cells for release of tumor necrosis factor α via MAP3K8

et al. 2018

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Dendritic cells (DCs) constantly sample peripheral tissues for antigens, which are subsequently ingested to derive peptides for presentation to T cells in lymph nodes. To do so, DCs have to traverse many different tissues with varying oxygen tensions. Additionally, DCs are often exposed to low oxygen tensions in tumors, where vascularization is lacking, as well as in inflammatory foci, where oxygen is rapidly consumed by inflammatory cells during the respiratory burst. DCs respond to oxygen levels to tailor immune responses to such low-oxygen environments. In the present study, we identified a mechanism of hypoxia-mediated potentiation of release of tumor necrosis factor α (TNF-α), a pro-inflammatory cytokine with important roles in both anti-cancer immunity and autoimmune disease. We show in human monocyte-derived DCs (moDCs) that this potentiation is controlled exclusively via the p38/mitogen-activated protein kinase (MAPK) pathway. We identified MAPK kinase kinase 8 (MAP3K8) as a target gene of hypoxia-induced factor (HIF), a transcription factor controlled by oxygen tension, upstream of the p38/MAPK pathway. Hypoxia increased expression of MAP3K8 concomitant with the potentiation of TNF-α secretion. This potentiation was no longer observed upon siRNA silencing of MAP3K8 or with a small molecule inhibitor of this kinase, and this also decreased p38/MAPK phosphorylation. However, expression of DC maturation markers CD83, CD86, and HLA-DR were not changed by hypoxia. Since DCs play an important role in controlling T-cell activation and differentiation, our results provide novel insight in understanding T-cell responses in inflammation, cancer, autoimmune disease and other diseases where hypoxia is involved.

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Tpl2 promotes neutrophil trafficking, oxidative burst, and bacterial killing

Cited by 16 publications

References 61 publications

Tpl2 Promotes Innate Cell Recruitment and Effector T Cell Differentiation To Limit Citrobacter rodentium Burden and Dissemination

Tpl2 Promotes Innate Cell Recruitment and Effector T Cell Differentiation To Limit Citrobacter rodentium Burden and Dissemination

Tpl2 Protects Against Fulminant Hepatitis Through Mobilization of Myeloid-Derived Suppressor Cells

Hypoxia potentiates monocyte-derived dendritic cells for release of tumor necrosis factor α via MAP3K8

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