Platelet PI3K Modulates Innate Leukocyte Extravasation during Acid-Induced Acute Lung Inflammation

Abstract

Introduction Blood platelets are increasingly recognized as modulators of leukocyte effector functions in various pathologies including acute lung injury (ALI). ALI is a life-threatening disease, caused by damage to the alveolar epi- and endothelium. Excessive accumulation of leukocytes leads to severe lung inflammation, resulting in impaired lung function and hypoxemia. Objective Since leukocyte migration is modulated by activated platelets and phosphatidylinositol 3-kinase (PI3K) signaling is involved in platelet function, we aimed to elucidate the effect of PI3K on platelet-mediated immune responses. Materials and Methods We generated a mouse model with a platelet-specific deletion of p85α, the most important regulatory subunit of the class IA PI3K, and evaluated platelet function and platelet–leukocyte interactions. Moreover, we analyzed the impact of platelet-specific p85α gene deficiency during sterile peritonitis and acid-induced ALI. Results In vitro analyses of platelets revealed that lack of p85α led to decreased downstream signaling and diminished expression of surface activation markers, for example, CD62P and CD63, as well as reduced platelet aggregation. Moreover, platelet PI3K essentially mediated direct interactions of platelets with monocytes and neutrophils. In mice, platelet-specific p85α deficiency prevented leukocyte infiltration into the peritoneum and the bronchoalveolar compartment during sterile peritonitis and ALI, respectively. Additionally, the release of the inflammatory cytokine interleukin-12/23 was diminished in platelet p85α-deficient mice during ALI. In contrast to PI3K, neither overexpression nor depletion of platelet phosphatase and tensin homolog, the endogenous antagonist of PI3K, significantly modulated platelet function. Conclusion Our data indicate a crucial role of platelet PI3K signaling for leukocyte extravasation upon inflammatory stimuli in various diseases models.

Antisense oligonucleotide targeting of thrombopoietin represents a novel platelet depletion method to assess the immunomodulatory role of platelets

“…Interestingly, in TPO ASO treated mice levels of Ly6C hi monocytes and macrophages were significantly reduced in the lung consistent with previous reports that platelets are essential for the recruitment of monocytes to sites of inflammation, 41,42 and necessary for effective inflammation resolution 43 . Of significance, in our model of lower airway dysbiosis, we found that platelet depletion by either TPO ASO treatment of anti‐CD42b resulted in the same impairment to monocyte and macrophage recruitment.…”

“…28,38 Following pulmonary inflammation, platelets are detected coupled to leukocytes in bronchoalveolar lavage fluid 39 and have been found to migrate into the extravascular compartment of the lung during allergen-induced airway inflammation. 40 Profiling of whole lung homogenates found that Cd41 mRNA was significantly reduced in TPO ASO-treated mice; for the recruitment of monocytes to sites of inflammation, 41,42 and necessary for effective inflammation resolution. 43 Of significance, in our model of lower airway dysbiosis, we found that platelet depletion by either TPO ASO treatment of anti-CD42b resulted in the same impairment to monocyte and macrophage recruitment.…”

Ribosomal Protein SA-Positive Neutrophil Elicits Stronger Phagocytosis and Neutrophil Extracellular Trap Formation and Subdues Pro-Inflammatory Cytokine Secretion Against Streptococcus suis Serotype 2 Infection

“…Inflammation caused by inappropriate neutrophil activation will result in serious damage to the host tissues. Consequently, functional conversion of neutrophils is regulated by numerous mechanisms (35)(36)(37). In recent years, there have been an increasing number of studies showing that neutrophil surface receptors play specific roles in the pathogenesis of some diseases and can affect its functions via various mechanisms.…”

Shear Stress Accumulation Enhances von Willebrand Factor-Induced Platelet P-Selectin Translocation in a PI3K/Akt Pathway-Dependent Manner

“…It was demonstrated that VWF-GPIbα signaling through PI3K and Akt was responsible for platelet integrin activation (Spater et al, 2018;Kral-Pointner et al, 2019). Thus, PI3K/Akt signaling might be involved in VWF-induced platelet P-selectin translocation because that P-selectin translocation was one of a series of platelet activation's landmark events, such as platelet morphology changes, integrin activation, particle release (Pselectin translocation, etc.…”

“…It is demonstrated that inhibiting VWF-GPIbα interaction can reduce effectively the force-induced platelet P-selectin translocation (Goto et al, 2000;Rahman and Hlady, 2021), while VWF-GPIbα signaling through PI3K/Akt participated in platelet integrin activation and high shear stress-induced platelet P-selectin translocation (Spater et al, 2018;Chen et al, 2019;Kral-Pointner et al, 2019). It is believed that catch-slip bond transition governs the interaction of VWF with GPIbα and retains but shifts the shear stress threshold in the cases of type 2B or 2M VWF mutations that result in bleeding disorders (Coburn et al, 2011).…”