Plasmacytoid Dendritic Cells Control Lung Inflammation and Monocyte Recruitment in Indirect Acute Lung Injury in Mice

Indirect acute lung injury (ALI, not caused by a direct insult to the lung) represents the first organ dysfunction in trauma patients, with nonpulmonary sepsis being the most common cause of indirect ALI. Dendritic cells (DCs) are thought to participate in a number of inflammatory lung diseases; however, their role in indirect ALI is currently not established. Using a clinically relevant model of indirect ALI induced in mice by hemorrhagic shock followed 24 hours later by polymicrobial septic challenge, we report that mature DC numbers were markedly increased in the lung during indirect ALI. DC depletion induced a significant increase in indirect ALI severity, which was associated with enhanced lung and plasma proinflammatory cytokine concentration and recruitment of proinflammatory CD115⁺ monocytes in response to increased lung monocyte chemotactic protein-1 production. Among the different DC subpopulations, plasmacytoid DCs, which were induced and activated in the lung during indirect ALI, were responsible for this effect because their specific depletion reproduced the observations made in DC-depleted mice. As the recruitment of monocytes to the lung plays a central deleterious role in the pathophysiology of indirect ALI, our data therefore position plasmacytoid DCs as important regulators of acute lung inflammation.Acute lung injury (ALI) and its most severe form, the acute respiratory distress syndrome (ARDS), are the two parts of a clinical syndrome defined by acute hypoxemic respiratory failure, bilateral pulmonary infiltrate attributable to edema, and normal cardiac filling pressures.¹Of those seriously injured trauma victims who survive the first hours immediately after injury, upwards of 50% develop some forms of multiple organ failure. In this respect, ALI is reported to be one of the most common forms of organ dysfunction in these individuals.^1,2 Every year, ALI and ARDS are thus the cause of more than 74,000 deaths in the United States.²This syndrome can be categorized into direct (pulmonary) and indirect (nonpulmonary) ALI. Epidemiologically, direct ALI accounts for 57% of all cases and is caused mainly by pneumonia, aspiration, and lung trauma. Indirect ALI accounts for the residual 43% with nonpulmonary sepsis being the most frequent underlying disease.³ Among all causes, sepsis is associated with the highest risk of progression to ALI (approximately 40%) and sepsis-associated ARDS carries the highest mortality rates from ARDS.^1,2,4 Importantly, patients developing ALI after nonpulmonary sepsis (indirect ALI) present with a higher mortality rate than patients with pulmonary sepsis (direct ALI).⁵Despite almost 35 years of intense investigation, the fundamental mechanisms that initiate and propagate lung injury have not yet been defined completely.¹ In particular, mechanisms leading to direct versus indirect ALI may be different, with pulmonary infections causing lung injury directly via the pathogen and host response versus nonpulmonary infections causing lung injury indirectly via systemic inflammation.¹ Moreover, findings from a number of studies suggest that “priming” of different cell types occurs and appears to play significant roles in mediating the increased inflammation associated with this injury.^1,6 However, despite a good understanding of the process that initiates and promotes host inflammation, little is known about the host immune cells that are responsible for the inhibition of the inflammatory response.Dendritic cells (DCs), both myeloid (mDCs) and plasmacytoid (pDCs), exist in the lung in relatively small numbers.^7,8 In this location, they are ideally positioned to play a central role in the immune response during infection/inflammation.^7,8 Indeed, a role for DCs has been shown in a number of lung inflammatory diseases in human (asthma, chronic obstructive pulmonary disease, lung cancer, or transplant rejection).⁷ Moreover, during ongoing inflammation, DCs migrate to the lung where they not only maintain and enhance local immune response, but also regulate this response.^7,9 Therefore, we hypothesized that DCs have a role in the pathophysiology of indirect ALI. We investigated this using a clinically relevant model of indirect ALI induced in mice by a hemorrhagic shock followed 24 hours later by a polymicrobial septic challenge.