Platelets promote pulmonary pull of polys

In this issue of Blood, Guo and colleagues¹  report the intriguing discovery of a unique proinflammatory role for platelet-derived Dickkopf-1 (Dkk1), a secreted antagonist of pulmonary epithelial repair programs that use the canonical Wnt/β-catenin pathway, in mouse models of acute lung injury.

Circulating platelets play important roles in the acute response to infection and inflammation, particularly in the lung. The role of platelets in this setting is executed, at least in part, through interactions with first-responder neutrophils. By example, platelets can serve as a sensor for foreign invaders like bacteria through Toll-like receptor (TLR; eg, TLR-4) signaling to detect foreign ligands, including bacterial lipopolysaccharide (LPS),²  and then report the threat to neutrophils. Platelets can also stimulate the formation of neutrophil extracellular traps, thereby participating in the response to microbial invasion.³  Now, Guo and coworkers demonstrate that the Wnt antagonist Dkk1, which is derived from activated platelets, disinhibits (and thus promotes) the influx of neutrophils into the lung parenchyma during the innate immune response to several different and clinically relevant acute insults. Whereas the Wnt/β-catenin pathway has been assigned important roles in embryonic development and carcinogenesis in the lung and elsewhere, recognition of its role in innate immune responses is relatively recent.

Platelets contain nearly all of the elements of the Wnt/β-catenin canonical pathway, but because they lack a nucleus, the β-catenin stabilized by Wnt ligation of a surface receptor is hypothesized to act through nontranscriptional mechanisms, such as the coupling of adhesion receptor activation with cytoskeletal changes transduced by actin.⁴  However, Dkk1 is also present in the α granules of platelets and, when released, its potential sphere of influence is substantial. Through its effects on osteoblast differentiation and function, Dkk1 from platelets or other cells can contribute to the balance between bone resorption and formation both basally and in the osteolytic lesions of multiple myeloma.^5,6  Circulating Dkk1 is primarily within or secreted by platelets, and is reversibly associated with platelet activation and endothelial activation in type 2 diabetes mellitus.⁷ 

The ability of platelet-secreted Dkk1 to potentiate neutrophilic infiltration appeared, according to the newly published work by Guo and colleagues,¹  to depend specifically on the upregulation of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 on the surface of alveolar epithelial cells. A similar role for signaling by Wnt in the transendothelial migration of monocytes has been described,⁸  but the new report by Guo and colleagues appears to be the first to show that an anucleate circulating cell can antagonize epithelial cell Wnt to facilitate lung infiltration of leukocytes. This novel report is therefore remarkable not only for revealing a fresh facet of the intersection between platelet biology and acute inflammation but also for unmasking and outlining the signaling underlying important repair processes active early on in the injured lung after any of a variety of insults.

The broad potential relevance of these findings for acute infectious and other cytokine- and chemokine-driven disease in the lung and perhaps beyond is underlined by the similarity of the findings from Guo et al¹  in model mice with viral pneumonia, bacterial pneumonia, or a tandem insult of LPS and ventilator trauma. Because the authors identified Dkk1 specifically as the culprit antagonist of the Wnt/β-catenin pathway, there is the testable and promising possibility that antagonizing the platelet-derived Dkk1 pathway for therapeutic benefit can attenuate injury and unmask repair programs. Neutralizing Dkk1 could, in theory, promote these ends without promiscuous and deleterious Wnt pathway activation, as might be the result of administering Wnt ligands, which are also now the subject of preclinical and clinical testing.