Podoplanin Drives Motility of Active Macrophage via Regulating Filamin C During Helicobacter pylori Infection

Abstract

Podoplanin (Pdpn) is a mucin-type transmembrane protein that has been implicated in multiple physiological settings including lymphangiogenesis, platelet aggregation, and cancer metastasis. Here, we reported an absence of Pdpn transcript expression in the resting mouse monocytic macrophages, RAW264.7 cells; intriguingly, a substantial upregulation of Pdpn was observed in activated macrophages following Helicobacter pylori or lipopolysaccharide stimulation. Pdpn-knockout macrophages demonstrated intact phagocytic and intracellular bactericidal activities comparable to wild type but exhibited impaired migration due to attenuated filopodia formation. In contrast, an ectopic expression of Pdpn augmented filopodia protrusion in activated macrophages. NanoString analysis uncovered a close dependency of Filamin C gene on the presence of Pdpn, highlighting an involvement of Filamin C in modulation of actin polymerization activity, which controls cell filopodia formation and migration. In addition, interleukin-1β production was significantly declined in the absence of Pdpn, suggesting a role of Pdpn in orchestrating inflammation during H. pylori infection besides cellular migration. Together, our findings unravel the Pdpn network that modulates movement of active macrophages.

Innate Immunity Crosstalk with Helicobacter pylori: Pattern Recognition Receptors and Cellular Responses

“…They are responsible for the polarization of T H 1 via secretions of IL-12 and IL-23 [ 56 ]. The importance of macrophages in H. pylori infection is highlighted by their marked increases in inflammatory markers, cell motility [ 57 ], and infiltration into the peritoneum as early as 2 days post-infection [ 58 ]. Furthermore, transient removal of CD11b + macrophage population was identified to reduce gastric pathology in H. pylori infected mice without altering the bacterial load, implying its critical role in gastric pathology [ 59 ].…”

The Role of Podoplanin in the Immune System and Inflammation

“… 37 Cheok et al also proposed that during Helicobacter pylori infection, podoplanin drives motility of active macrophages via regulating Filamin C, a member of actin-crosslinking protein family that stabilizes and links actin web to the cell membrane. 39 , 40 They demonstrated that podoplanin may promote Filamin C transactivation through interacting with the ERM complex and activating Rho GTPase signaling pathway, but further investigation is required to confirm this notion. 39 …”

“… 39 , 40 They demonstrated that podoplanin may promote Filamin C transactivation through interacting with the ERM complex and activating Rho GTPase signaling pathway, but further investigation is required to confirm this notion. 39 …”

An Overview of Helicobacter pylori Survival Tactics in the Hostile Human Stomach Environment

“…Targeting H. pylori-host interaction has also seen major advancement, especially in the alleviation of chronic inflammation. It has been identified that H. pylori induces expression of an inflammatory protein, podoplanin, via LPS to induce strong proinflammatory IL-1β secretion from macrophages [88]. Podoplanin has been proposed as a treatment target in chronic inflammatory rheumatoid arthritis [89].…”