Pleural Resident Macrophages and Pleural IRA B Cells Promote Efficient Immunity Against Pneumonia by Inducing Early Pleural Space Inflammation

Abstract

Airway infection is a major cause of mortality worldwide. The identification of new mechanisms aiding in effective host immune response is therefore required. Here, we show that the specific depletion of the pleural immune cell compartment during bacterial pneumonia resulted in a reduced pulmonary immune response and increased mortality in mice. Bacterial airway infection provoked early pleural space (PS) inflammation characterized by innate response activator (IRA) B cell development and pleural large resident macrophage (LRM) necroptosis, the repopulation of LRMs being driven by cellular proliferation in situ. Necroptotic LRMs amplified PS inflammation by stimulating pleural Mincle-expressing macrophages whereas IRA B cells contributed partially to GM-CSF-induced PS inflammation. Upon pulmonary infection, the induction of PS inflammation resulted in reduced bacterial burden whereas the specific depletion of pleural resident macrophages led to increased mortality and bacterial burden and reduced pulmonary immunity. Moreover, mice in which B cells were unable to produce GM-CSF exhibited reduced CD103+ dendritic cells and reduced CD4+ T cell numbers in the draining lymph node. Altogether, our results describe a previously unrecognized mechanism of pleural space inflammation necessary for effective protection against bacterial airway infection.

Pleural macrophages translocate to the lung during infection to promote improved influenza outcomes

“…Other studies have focused on the roles that large serosal macrophage migration from the pleural, pericardial and peritoneal cavities play in the health of the organs they envelop [22-24, 37]. None to date, have tested whether small serosal macrophages have the capacity to translocate to the visceral organs.…”

“…While we were preparing this manuscript, Bénard et al . described increased bacterial burden and mortality upon PM depletion in a mouse model of bacterial pneumonia (37). Unlike in Bénard et al ., where bacterial burdens increased upon PM depletion and resulted in increased mortality, we saw increased disease severity without differences in viral titers between PM-depleted and control groups after IAV infection.…”

“…Similar observations have been seen in patients infected with IAV and/or bacteria (41, 42, 48-50). Additionally, pleural space inflammation can provide protection against bacterial lung infection (37). Following viral infection, patients are left more vulnerable to subsequent pneumonia, but PMs may limit inflammation after infection and decrease susceptibility to pneumonia.…”

“…However, no proinflammatory cytokines were increased in the lung between the infected groups (Figure 6D), though PM-depletion caused an increase in serum IFN-γ levels in response to lung IAV infection. Other studies have focused on the roles that large serosal macrophage migration from the pleural, pericardial and peritoneal cavities play in the health of the organs they envelop [22][23][24]37]. None to date, have tested whether small serosal macrophages have the capacity to translocate to the visceral organs.…”

“…Previous studies have shown conflicting evidence for a role of cavity macrophages in models of liver, heart and intestinal injury, showcasing differences in recruitment, wound repair, and weight loss [22][23][24]36]. Another study suggested a role for PMs in bacterial clearance in bacterial pneumonia [37]. However, no study to date has 5A).…”