TLR-independent neutrophil-derived IFN-γ is important for host resistance to intracellular pathogens

Sturge, Carolyn R.; Benson, Alicia; Raetz, Megan; Wilhelm, Cara L.; Mirpuri, Julie; Vitetta, Ellen S.; Yarovinsky, Felix

doi:10.1073/pnas.1307868110

Cited by 107 publications

(114 citation statements)

References 53 publications

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“…Induction of Ifng expression in the cecal mucosa at 2 days after oral S. Typhimurium infection is MYD88 dependent (18). Similarly, IFN-␥ production elicited by neutrophils recovered from the peritoneal cavities of mice 5 days after intraperitoneal infection with Toxoplasma gondii is MYD88 dependent (31). Collectively, these data suggest that neutrophils are an important cellular source of IFN-␥ during the innate phase of a bacterial infection.…”

Section: Discussionmentioning

confidence: 79%

Neutrophils Are a Source of Gamma Interferon during Acute Salmonella enterica Serovar Typhimurium Colitis

et al. 2014

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Gamma interferon (IFN-␥) is an important driver of intestinal inflammation during colitis caused by Salmonella enterica serovar Typhimurium. Here we used the mouse colitis model to investigate the cellular sources of IFN-␥ in the cecal mucosa during the acute phase of an S. Typhimurium infection. While IFN-␥ staining was detected in T cells, NK cells, and inflammatory monocytes at 2 days after infection, the majority of IFN-␥-positive cells in the cecal mucosa were neutrophils. Furthermore, neutrophil depletion blunted mucosal Ifng expression and reduced the severity of intestinal lesions during S. Typhimurium infection. We conclude that neutrophils are a prominent cellular source of IFN-␥ during the innate phase of S. Typhimurium-induced colitis. Individuals with primary immunodeficiencies impairing production of gamma interferon (IFN-␥) or IFN-␥ signaling present in childhood with disseminated bacterial infections. The vast majority of these infections are caused by two bacterial pathogens: nontyphoidal Salmonella serovars and weakly virulent Mycobacterium species (1). Nontyphoidal Salmonella serovars, such as S. enterica serovar Typhimurium, cause a localized gastroenteritis in immunocompetent individuals, which is characterized by acute intestinal inflammation and diarrhea (reviewed in references 2 and 3). The importance of innate immune responses during gastroenteritis is illustrated by the rapid onset of intestinal inflammation, which gives rise to symptoms within 24 h of ingesting S. Typhimurium (4). A histopathological hallmark of S. Typhimurium-induced gastroenteritis is a severe acute infiltrate of neutrophils in the ileal and colonic mucosae (5, 6). Studies using a mouse model of S. Typhimurium-induced colitis show that in animals lacking IFN-␥, the severity of intestinal inflammation is markedly attenuated (7,8).Conventional wisdom holds that IFN-␥ is produced during the innate phase of a bacterial infection by natural killer (NK) cells and NKT cells (reviewed in reference 9) while CD4 ϩ and CD8 ϩ T cells become the principal cellular sources at later stages, which are governed by adaptive immune responses (reviewed in references 10 and 11). Consistent with this idea, splenic NK cells are a prominent cellular source of innate IFN-␥ production in models of systemic S. Typhimurium infection (12-14). Furthermore, CD1D-restricted NKT cells contribute to innate IFN-␥ production in the livers and spleens of mice with disseminated S. Typhimurium infection (15, 16). However, the identities of the innate immune cells contributing to early IFN-␥ production in the intestinal mucosa have not been fully resolved. The goal of this study was to identify the cellular sources of innate IFN-␥ production in the intestinal mucosa during S. Typhimurium-induced colitis. MATERIALS AND METHODSBacterial strains and culture conditions. S. Typhimurium strain IR715 is a fully virulent, nalidixic acid-resistant derivative of wild-type isolate ATCC 14028 (American Type Culture Collection) (17). Bacteria were cultured overnight ae...

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Section: Discussionmentioning

confidence: 79%

Neutrophils Are a Source of Gamma Interferon during Acute Salmonella enterica Serovar Typhimurium Colitis

et al. 2014

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“…Mice were injected intraperitoneally with purified anti-mouse IFN-γ (clone XMG1.2) or an appropriate isotype control (both purchased from BioXcell) at a dose of 250 μg 24 h and 30 min before subcutaneous injection of entolimod, as previously described (54). Livers and blood were collected at the indicated times after entolimod injection for assessing expression of CXCL9 and CXCL10 by ELISA, as described above.…”

Section: Methodsmentioning

confidence: 99%

Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 ⁺ T-cell axis

Brackett

Kojouharov

Veith

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Activation of an anticancer innate immune response is highly desirable because of its inherent ability to generate an adaptive antitumor T-cell response. However, insufficient safety of innate immune modulators limits clinical use to topical applications. Tolllike receptor 5 (TLR5) agonists are favorably positioned as potential systemic immunotherapeutic agents because of unusual tissue specificity of expression, uniquely safe profile of induced cytokines, and antitumor efficacy demonstrated in a number of animal models. Here, we decipher the molecular and cellular events underlying the metastasis suppressive activity of entolimod, a clinical stage TLR5 agonist that activates NF-κB-, AP-1-, and STAT3-driven immunomodulatory signaling pathways specifically within the liver. Used as a single agent in murine colon and mammary metastatic cancer models, entolimod rapidly induces CXCL9 and -10 that support homing of blood-borne CXCR3-expressing NK cells to the liver predominantly through an IFN-γ signaling independent mechanism. NK cell-dependent activation of dendritic cells is followed by stimulation of a CD8 + T-cell response, which exert both antimetastatic effect of entolimod and establishment of tumor-specific and durable immune memory. These results define systemically administered TLR5 agonists as organ-specific immunoadjuvants, enabling efficient antitumor vaccination that does not depend on identification of tumor-specific antigens.cancer immunotherapy | liver | colorectal cancer | breast cancer | innate immunity R ecent advancements in the field of anticancer immunotherapy have been primarily focused on development of T-cellbased approaches because of recognition of the inherent ability of adaptive immunity to efficiently eradicate neoplastic disease (1, 2). Innate immune responses play important roles in T-cell activation, but their potential relevance for prevention and treatment of cancer remains underappreciated (3-5). Toll-like receptors (TLRs) are gaining attention as potential therapeutic targets capable of stimulating antitumor immunity by initiating innate responses (6) and subsequent adaptive T-cell-based immunity (7). Although proof-ofprinciple for this concept has been demonstrated with agonists of several TLRs (TLR3, -7, and -9) (8), only one, the TLR7 agonist Imiquimod, has been approved for clinical use [however, this is limited to topical treatment of basal cell carcinoma (9)]. The major clinical limitations of many TLR agonists are the risk of dose-limiting toxicities associated with their systemic delivery (10-12) and metastasis stimulation (13-15). Furthermore, some previously investigated TLR agonists are restricted to injection directly into tumor tissue (3,(16)(17)(18), an approach that will likely have limited therapeutic value in cancer patients with metastatic disease.TLR5 is unique among TLRs as a potential target for systemic anticancer immunotherapy. Studies have shown that the only known natural TLR5 agonist, flagellin, flagellin-expressing Salmonella bacteria, and a pharmacolog...

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“…Recent evidence illustrates that in both wild-type (WT) and TLR11-deficient mice, neutrophils are the dominant cell type responsible for early IFN-␥ responses (52). The level of IFN-␥ observed in each neutrophil is low compared to that of activated NK or T cells (52), and yet neutrophils are known to congregate in large numbers at the site of acute toxoplasma infection (49,(52)(53)(54). Depletion of neutrophils in TLR11-deficient mice resulted in acute mortality that can be delayed with injections of recombinant IFN-␥ (52).…”

Section: Ifn-␥-producing Cells: From T To Nk Cells and Neutrophilsmentioning

confidence: 99%

Complex Immune Cell Interplay in the Gamma Interferon Response during Toxoplasma gondii Infection

2014

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Toxoplasma gondii is an obligate intracellular parasite of clinical importance, especially in immunocompromised patients. Investigations into the immune response to the parasite found that T cells are the primary effector cells regulating gamma interferon (IFN-␥)-mediated host resistance. However, recent studies have revealed a critical role for the innate immune system in mediating host defense independently of the T cell responses to the parasite. This body of knowledge is put into perspective by the unifying theme that immunity to the protozoan parasite requires a strong IFN-␥ host response. In the following review, we discuss the role of IFN-␥-producing cells and the signals that regulate IFN-␥ production during T. gondii infection.

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TLR-independent neutrophil-derived IFN-γ is important for host resistance to intracellular pathogens

Cited by 107 publications

References 53 publications

Neutrophils Are a Source of Gamma Interferon during Acute Salmonella enterica Serovar Typhimurium Colitis

Neutrophils Are a Source of Gamma Interferon during Acute Salmonella enterica Serovar Typhimurium Colitis

Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 ⁺ T-cell axis

Complex Immune Cell Interplay in the Gamma Interferon Response during Toxoplasma gondii Infection

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TLR-independent neutrophil-derived IFN-γ is important for host resistance to intracellular pathogens

Cited by 107 publications

References 53 publications

Neutrophils Are a Source of Gamma Interferon during Acute Salmonella enterica Serovar Typhimurium Colitis

Neutrophils Are a Source of Gamma Interferon during Acute Salmonella enterica Serovar Typhimurium Colitis

Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 + T-cell axis

Complex Immune Cell Interplay in the Gamma Interferon Response during Toxoplasma gondii Infection

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Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 ⁺ T-cell axis