Roles of STAT3 in Protein Secretion Pathways during the Acute-Phase Response

Ahyi, Ayele-Nati N.; Quinton, Lee J.; Jones, Matthew R.; Ferrari, Joseph D.; Pepper-Cunningham, Zachary A.; Mella, Juan Rodolfo; Remick, Daniel G.; Mizgerd, Joseph P.

doi:10.1128/iai.01332-12

Cited by 27 publications

(24 citation statements)

References 28 publications

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“…Recently, our laboratory has also shown that the APR is necessary for survival during a gram-positive Streptococcus pneumoniae infection (11). Indeed, these studies and others have now revealed over 1,000 gene changes and numerous biological processes in the liver that are altered during pneumonia, any or all of which could influence disease outcome (6,11,36). In those studies, CRE 1 mice showed decreased complement deposition and opsonophagocytosis of pneumococcus, leading to increased bacteremia, suggesting that one function of the APR is to limit dissemination of infection.…”

Section: Discussionmentioning

confidence: 99%

The Lung-Liver Axis: A Requirement for Maximal Innate Immunity and Hepatoprotection during Pneumonia

Hilliard

Allen

Traber

et al. 2015

Am J Respir Cell Mol Biol

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The hepatic acute-phase response (APR), stimulated by injury or inflammation, is characterized by significant changes in circulating acute-phase protein (APP) concentrations. Although individual functions of liver-derived APPs are known, the net consequence of APP changes is unclear. Pneumonia, which induces the APR, causes an inflammatory response within the airspaces that is coordinated largely by alveolar macrophages and is typified by cytokine production, leukocyte recruitment, and plasma extravasation, the latter of which may enable delivery of hepatocyte-derived APPs to the infection site. To determine the functional significance of the hepatic APR during pneumonia, we challenged APR-null mice lacking hepatocyte signal transducer and activator of transcription 3 (STAT3) and v-rel avian reticuloendotheliosis viral oncogene homolog A (RelA) with Escherichia coli in the airspaces. APR-null mice displayed ablated APP induction, significantly increased mortality, liver injury and apoptosis, and a trend toward increased bacterial burdens. TNF-a neutralization reversed hepatotoxicity, but not mortality, suggesting that APR-dependent survival is not solely due to hepatoprotection. After a milder (nonlethal) E. coli infection, hepatocyte-specific mutations decreased APP concentrations and pulmonary inflammation in bronchoalveolar lavage fluid. Cytokine expression in airspace macrophages, but not other airspace or circulating cells, was significantly dependent on APP extravasation into the alveoli. These data identify a novel signaling axis whereby the liver response enhances macrophage activation and pulmonary inflammation during pneumonia. Although hepatic acute-phase changes directly curb injury induced by TNF-a in the liver itself, APPs downstream of these same signals promote survival in association with innate immunity in the lungs, thus demonstrating a critical role for the lung-liver axis during pneumonia.

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Section: Discussionmentioning

confidence: 99%

The Lung-Liver Axis: A Requirement for Maximal Innate Immunity and Hepatoprotection during Pneumonia

Hilliard

Allen

Traber

et al. 2015

Am J Respir Cell Mol Biol

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“…Additionally, E. coli pneumonia models induce large amounts of lung injury necessary to induce plasma protein (and thus APP) extravasation into the airspaces, which is key in understanding how the liver response to sepsis can directly influence local lung defense. Because liver STAT3 activation is required for maximal APR induction (24,25,30,31), we measured the concentrations of two representative, circulating APPs: serum amyloid A (SAA) and serum amyloid P (SAP). In WT mice, the concentrations of both SAA and SAP in serum were induced dramatically above baseline with LPS pretreatment alone (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Induced by the host defense cytokines tumor necrosis factor alpha (TNF-␣), interleukin-1 (IL-1), and IL-6 (20), the APR is characterized by significant changes in circulating levels of acute-phase proteins (APPs) (19,21,22). While it is well appreciated that sepsis can cause pulmonary immunosuppression and pneumonia susceptibility (5, 7-15), it is unclear whether or how preexisting liver activation (i.e., sepsis-induced APR) modulates subsequent responses to local lung infections.Signal transducer and activator of transcription-3 (STAT3) is one of two transcription factors (along with NF-B RelA) required for induction of a strong hepatic APR during pneumonia (23)(24)(25). Several lines of evidence implicate beneficial roles for liver-derived APPs during pneumonia (26)(27)(28)(29).…”

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confidence: 99%

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Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia

et al. 2015

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e Pneumonia and infection-induced sepsis are worldwide public health concerns. Both pathologies elicit systemic inflammation and induce a robust acute-phase response (APR). Although APR activation is well regarded as a hallmark of infection, the direct contributions of liver activation to pulmonary defense during sepsis remain unclear. By targeting STAT3-dependent acute-phase changes in the liver, we evaluated the role of liver STAT3 activity in promoting host defense in the context of sepsis and pneumonia. We employed a two-hit endotoxemia/pneumonia model, whereby administration of 18 h of intraperitoneal lipopolysaccharide (LPS; 5 mg/kg of body weight) was followed by intratracheal Escherichia coli (10 6 CFU) in wild-type mice or those lacking hepatocyte STAT3 (hepSTAT3 ؊/؊ ). Pneumonia alone (without endotoxemia) was effectively controlled in the absence of liver STAT3. Following endotoxemia and pneumonia, however, hepSTAT3 ؊/؊ mice, with significantly reduced levels of circulating and airspace acute-phase proteins, exhibited significantly elevated lung and blood bacterial burdens and mortality. These data suggested that STAT3-dependent liver responses are necessary to promote host defense. While neither recruited airspace neutrophils nor lung injury was altered in endotoxemic hepSTAT3 ؊/؊ mice, alveolar macrophage reactive oxygen species generation was significantly decreased. Additionally, bronchoalveolar lavage fluid from this group of hepSTAT3 ؊/؊ mice allowed greater bacterial growth ex vivo. These results suggest that hepatic STAT3 activation promotes both cellular and humoral lung defenses. Taken together, induction of liver STAT3-dependent gene expression programs is essential to countering the deleterious consequences of sepsis on pneumonia susceptibility. Sepsis is a complex immunopathological syndrome defined by the systemic inflammatory response to infection and is a leading contributor to morbidity and mortality in intensive care units as evidenced by approximately 750,000 cases per year (2% of all hospital admissions) (1-3). This multifaceted, systemic inflammatory response can be further complicated by organ dysfunction (severe sepsis) and hypotension (septic shock), all of which lead to a complex, variable syndrome with mortality rates between 30 and 50% (4). While pneumonia is the leading cause of sepsis, with about one-half of all sepsis cases originating as respiratory infections (2), sepsis also greatly increases a patient's subsequent susceptibility to bacterial pneumonia (5). In fact, 10 to 30% of mechanically ventilated, septic shock patients develop ventilator-associated pneumonia (6). This positive association extends beyond ventilator-related circumstances and has been corroborated experimentally by multiple studies demonstrating deleterious effects of sepsis and/or endotoxemia on pneumonia outcomes (7-15). With the rapid increase in prevalence of drugresistant pathogens and the limited treatment options available, there is a growing need to develop novel pharmaceutical interventions...

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“…Intrapulmonary delivery of bacteria or bacterial products elicits a rapid and robust acute phase response (25, 37, 78, 79). The liver alters expression of more than a thousand genes during pneumococcal pneumonia (79).…”

Section: Resistance: Cell-specific Roles That Initiate Direct and Amentioning

confidence: 99%

Dynamics of Lung Defense in Pneumonia: Resistance, Resilience, and Remodeling

Quinton

Mizgerd

2015

Annu. Rev. Physiol.

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Pneumonia is initiated by microbes in the lung, but physiological processes integrating responses across diverse cell types and organ systems dictate the outcome of respiratory infection. Resistance, or actions of the host to eradicate living microbes, in the lungs involves a combination of innate and adaptive immune responses triggered by air-space infection. Resilience, or the ability of the host tissues to withstand the physiologically damaging effects of microbial and immune activities, is equally complex, precisely regulated, and determinative. Both immune resistance and tissue resilience are dynamic and change throughout the lifetime, but we are only beginning to understand such remodeling and how it contributes to the incidence of severe pneumonias, which diminishes as childhood progresses and then increases again among the elderly. Here, we review the concepts of resistance, resilience, and remodeling as they apply to pneumonia, highlighting recent advances and current significant knowledge gaps.

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Roles of STAT3 in Protein Secretion Pathways during the Acute-Phase Response

Cited by 27 publications

References 28 publications

The Lung-Liver Axis: A Requirement for Maximal Innate Immunity and Hepatoprotection during Pneumonia

The Lung-Liver Axis: A Requirement for Maximal Innate Immunity and Hepatoprotection during Pneumonia

Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia

Dynamics of Lung Defense in Pneumonia: Resistance, Resilience, and Remodeling

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