In Vivo Depletion of CD206+ M2 Macrophages Exaggerates Lung Injury in Endotoxemic Mice

Abstract

Although phenotypically polarized macrophages are now generally classified into two major subtypes termed proinflammatory M1 and anti-inflammatory M2 macrophages, a contributory role of lung M2 macrophages in the pathophysiological features of acute lung injury is not fully understood. Herein, we show in an endotoxemic murine model that M2 macrophages serve as key anti-inflammatory cells that play a regulatory role in the severity of lung injury. To study whether M2 macrophages can modify inflammation, we depleted M2 macrophages from lungs of CD206-diphtheria toxin (DT) receptor transgenic (Tg) mice during challenge with lipopolysaccharide. The i.p. administration of DT depleted CD206-positive cells in bronchoalveolar lavage fluid. The use of M2 macrophage markers Ym1 and arginase-1 identified pulmonary CD206-positive cells as M2 macrophages. A striking increase in neutrophils in bronchoalveolar lavage fluid cell contents was found in DT-treated CD206-DT receptor Tg mice. In CD206-DT receptor Tg mice given DT, endotoxin challenge exaggerated lung inflammation, including up-regulation of proinflammatory cytokines and increased histological lung damage, but the endotoxemia-induced increase in NF-κB activity was significantly reduced, suggesting that M2 phenotype-dependent counteraction of inflammatory insult cannot be attributed to the inhibition of the NF-κB pathway. Our results indicate a critical role of CD206-positive pulmonary macrophages in triggering inflammatory cascade during endotoxemic lung inflammation.

Epigenetic modifiers reduce inflammation and modulate macrophage phenotype during endotoxemia-induced acute lung injury

“…To understand the molecular changes that occur during treatment with Aza+TSA, we characterized M1 and M2 macrophages in LPS-induced BMDMs, and found significantly reduced expression of the M1 markers CD40, CD14 and NOS2, and increased expression of the M2 surface markers CD23, CD124 and CD206 in treated versus untreated cells. These findings further support the previous observations of distinct epigenetic reprogramming that is switched on in favor of an antiinflammatory subtype of M2 macrophages, which may prove beneficial in arresting the inflammatory cytokine response in sepsis (Kambara et al, 2015). Future experiments are required to define the molecular mechanisms underlying M1 and M2 plasticity of macrophages upon treatment with Aza+TSA.…”

Neonatal Pulmonary Macrophage Depletion Coupled to Defective Mucus Clearance Increases Susceptibility to Pneumonia and Alters Pulmonary Immune Responses

“…This feature is similar to the neutrophilia reported in MAFIA mice, a different model of macrophage depletion (18), and clodronate liposome-induced MF depletion (19). Increased neutrophil counts in BAL were also found in a model specifically designed to reduce M2 MFs using CD206-dependent Cre recombination (26). Kambara and colleagues (26) speculated that the neutrophilia reflected the disruption of the normal antiinflammatory role of M2 macrophage populations.…”

“…Increased neutrophil counts in BAL were also found in a model specifically designed to reduce M2 MFs using CD206-dependent Cre recombination (26). Kambara and colleagues (26) speculated that the neutrophilia reflected the disruption of the normal antiinflammatory role of M2 macrophage populations. In parallel, proinflammatory mediators derived from DTA 1 , apoptotic MFs also could contribute to this phenomenon (27).…”

Adipose tissue macrophages in non-rodent mammals: a comparative study

“…Several types of tissue-resident macrophages express CD206 in the mouse and the human, including ATMs (Aron-Wisnewsky et al 2009;Dupasquier et al 2006;Haase et al 2014;Svensson-Arvelund et al 2015;Titos et al 2011;Zeyda et al 2007). The immune functions of CD206 are not yet fully understood; for instance, its absence increases the random migration of macrophages and results in the up-regulation of proinflammatory cytokine production in the mouse (Kambara et al 2015). The lack of CD206 also results in the elevated serum level of inflammatory proteins, suggesting that it has a role in the resolution of inflammation by clearing inflammatory molecules from the blood (Lee et al .…”