Stimulation of Lung Innate Immunity Protects against Lethal Pneumococcal Pneumonia in Mice

Clement, Cecilia; Evans, Scott E.; Evans, Christopher M.; Hawke, David H.; Kobayashi, Ryûji; Reynolds, Paul; Moghaddam, Seyed Javad; Scott, Brenton L.; Melicoff, Ernestina; Adachi, Roberto; Dickey, Burton F.; Tuvim, Michael J.

doi:10.1164/rccm.200607-1038oc

Cited by 95 publications

(208 citation statements)

References 55 publications

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“…Previous reports documented that NTHi expresses multiple TLR agonists, including those for TLR3, TLR4, and TLR7 (5,(34)(35)(36). In addition, previous observations, that the pre-exposure of mice to NHTi lysate confers protection against challenge with a lethal dose of live Streptococcus pneumonia through the stimulation of the lung innate immune response, are relevant here (37,38). Nonetheless, our results clearly suggest that TLR2 is the main TLR involved in NTHi-induced inflammatory responses in A549 cells.…”

Section: Discussionsupporting

confidence: 57%

Antiinflammatory Role of MUC1 Mucin during Infection with NontypeableHaemophilus influenzae

Kyo

Kato

Park

et al. 2012

Am J Respir Cell Mol Biol

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MUC1 (or Muc1 in nonhuman species) is a membrane-tethered mucin expressed on the apical surface of mucosal epithelia (including those of the airways) that suppresses Toll-like receptor (TLR) signaling. We sought to determine whether the anti-inflammatory effect of MUC1 is operative during infection with nontypeable Haemophilus influenzae (NTHi), and if so, which TLR pathway was affected. Our results showed that: (1) a lysate of NTHi increased the early release of IL-8 and later production of MUC1 protein by A549 cells in dose-dependent and time-dependent manners, compared with vehicle control; (2) both effects were attenuated after transfection of the cells with a TLR2-targeting small interfering (si) RNA, compared with a control siRNA; (3) the NTHi-induced release of IL-8 was suppressed by an overexpression of MUC1, and was enhanced by the knockdown of MUC1; (4) the TNF-a released after treatment with NTHi was sufficient to up-regulate MUC1, which was completely inhibited by pretreatment with a soluble TNF-a receptor; and (5) primary murine tracheal surface epithelial (MTSE) cells from Muc1 knockout mice exhibited an increased in vitro production of NTHi-stimulated keratinocyte chemoattractant compared with MTSE cells from Muc1-expressing animals. These results suggest a hypothetical feedback loop model whereby NTHi activates TLRs (mainly TLR2) in airway epithelial cells, leading to the increased production of TNF-a and IL-8, which subsequently up-regulate the expression of MUC1, resulting in suppressed TLR signaling and decreased production of IL-8. This report is the first, to the best of our knowledge, demonstrating that the inflammatory response in airway epithelial cells during infection with NTHi is controlled by MUC1 mucin, mainly through the suppression of TLR2 signaling.

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Section: Discussionsupporting

confidence: 57%

Antiinflammatory Role of MUC1 Mucin during Infection with NontypeableHaemophilus influenzae

Kyo

Kato

Park

et al. 2012

Am J Respir Cell Mol Biol

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“…[18][19][20][21][22] Given the relative tolerance of lung epithelial cells to immunosuppressive therapies 23,24 and our observation that inducible resistance persists despite leukocyte depletion, [25][26][27] we hypothesized that this strategy could protect against pneumonia in the setting of leukemia and leukemia therapy. Here, we present evidence that inducible resistance persists in vitro and in vivo, despite exposure to leukemia and common antileukemia chemotherapy and propose this novel approach as a means to improve survival of patients with AML/MDS.…”

Section: Introductionmentioning

confidence: 99%

Inducible epithelial resistance protects mice against leukemia-associated pneumonia

Leiva‐Juárez

Ware

Kulkarni

et al. 2016

Blood

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“…Interestingly, the synergistic antimicrobial effect of TLR2/6 and TLR9 agonists was lost when these agonists were administered individually in mice (28,29). This effect was dependent on the classic TLR-MyD88 signaling pathway, but was not dependent on the presence of leukocytes, suggesting that airway epithelial cells are capable of inducing the TLR agonist response (36,37). Furthermore, the synergistic effect of TLR9 agonists with TLR2/6 agonists was greatest with Class C oligodeoxynucleotides compared with Class A or B oligodeoxynucleotides, possibly because of the induction by Class C of interferons and the transcription of cytokines via NF-kB, compared with either interferons (Class A) or NF-kB-related cytokines (Class B) alone (38).…”

Section: Discussionmentioning

confidence: 98%

Toll-Like Receptor–2/6 and Toll-Like Receptor–9 Agonists Suppress Viral Replication but Not Airway Hyperreactivity in Guinea Pigs

Drake

Evans

Dickey

et al. 2013

Am J Respir Cell Mol Biol

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Respiratory virus infections cause airway hyperreactivity (AHR). Preventative strategies for virus-induced AHR remain limited. Toll-like receptors (TLRs) have been suggested as a therapeutic target because of their central role in triggering antiviral immune responses. Previous studies showed that concurrent treatment with TLR2/6 and TLR9 agonists reduced lethality and the microbial burden in murine models of bacterial and viral pneumonia. This study investigated the effects of TLR2/6 and TLR9 agonist pretreatment on parainfluenza virus pneumonia and virus-induced AHR in guinea pigs in vivo. Synthetic TLR2/6 lipopeptide agonist Pam 2 CSK 4 and Class C oligodeoxynucleotide TLR9 agonist ODN2395, administered in combination 24 hours before virus infection, significantly reduced viral replication in the lung. Despite a fivefold reduction in viral titers, concurrent TLR2/6 and TLR9 agonist pretreatment did not prevent virus-induced AHR or virus-induced inhibitory M2 muscarinic receptor dysfunction. Interestingly, the TLR agonists independently caused non-M2-dependent AHR. These data confirm the therapeutic antiviral potential of TLR agonists, while suggesting that virus inhibition may be insufficient to prevent virus-induced airway pathophysiology. Furthermore, TLR agonists independently cause AHR, albeit through a distinctly different mechanism from that of parainfluenza virus.

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Stimulation of Lung Innate Immunity Protects against Lethal Pneumococcal Pneumonia in Mice

Abstract: We infer that protection derives from stimulation of local innate immune mechanisms, and that activated lung epithelium is the most likely cellular effector of this response. Augmentation of innate antimicrobial defenses of the lungs might have therapeutic value.

Cited by 95 publications

References 55 publications

Antiinflammatory Role of MUC1 Mucin during Infection with NontypeableHaemophilus influenzae

Antiinflammatory Role of MUC1 Mucin during Infection with NontypeableHaemophilus influenzae

Inducible epithelial resistance protects mice against leukemia-associated pneumonia

Toll-Like Receptor–2/6 and Toll-Like Receptor–9 Agonists Suppress Viral Replication but Not Airway Hyperreactivity in Guinea Pigs

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