Recent Advances in the Discovery and Function of Antimicrobial Molecules in Platelets

Abstract

The conventional function described for platelets is maintaining vascular integrity. Nevertheless, increasing evidence reveals that platelets can additionally play a crucial role in responding against microorganisms. Activated platelets release molecules with antimicrobial activity. This ability was first demonstrated in rabbit serum after coagulation and later in rabbit platelets stimulated with thrombin. Currently, multiple discoveries have allowed the identification and characterization of PMPs (platelet microbicidal proteins) and opened the way to identify kinocidins and CHDPs (cationic host defense peptides) in human platelets. These molecules are endowed with microbicidal activity through different mechanisms that broaden the platelet participation in normal and pathologic conditions. Therefore, this review aims to integrate the currently described platelet molecules with antimicrobial properties by summarizing the pathways towards their identification, characterization, and functional evaluation that have promoted new avenues for studying platelets based on kinocidins and CHDPs secretion.

Keywords: CHDPs (cationic host defense peptides); kinocidins; platelet microbicidal proteins (PMP); platelets.

Figure 1

Classification of antimicrobial molecules in platelets. In rabbit and human platelets, antimicrobial molecules are chronologically grouped according to species, structure, or function (left to right). In rabbits, only a serum component (PC-III) and the platelet microbicidal proteins (PMP) not induced and induced by thrombin (tPMP) are found. PMP1 and tPMP-1 are orthologous with the human kinocidin CXCL4 or Platelet Factor 4 (PF-4). Some human kinocidins or kinocidin-derived fragments are primarily produced by platelets (highlighted in blue). In the group of cationic host defense peptides (CHDPs), both human neutrophil peptides 1 (HNP-1), human beta-defensins (HBD 1-3), and cathelicidin (LL-37) belong to this category. Currently, a single RNAse with antimicrobial activity (RNAse 7) is found in this classification.

Figure 2

Comparative analysis of PMP-1 and human hPF4. (A) Comparative alignment of the primary structure of PMP-1 (rabbit) and hPF4 (human) generated with Clustal Omega and visualized with Jalview and Mview. hPF4 sequence was employed as a template. The total coverage percentage and identity are depicted on the left side. The predicted structure for PMP-1 with JPred of Jalview is indicated in the middle. The green arrows and red segment indicate the β-sheets and α-helices, respectively. The identity per base is represented in the gray scheme by the color intensity. (B) Left side, predicted structure for each protein obtained with SWISS-MODEL and visualized in RasMol in colors according to their structures. Both overlapping structures are visible in the center; the microbicidal domain is indicated in the solid blue line box and the chemokine domain in the dotted red line box. A dotted line indicates disulfide bonds. The human hPF4 is colored in green and PMP-1 of rabbit in pink. On the right side, a zoom of each domain. The chemokine domain was rotated to the right for more precise visualization of this structure.

Figure 3

The activity of platelet antimicrobial chemokines/kinocidins. Nonactivated resting platelets store antimicrobial chemokines/kinocidins. Highlighted in blue in the box are those mainly produced by platelets (CXCL-4, CXCL-7, and CCL-5) and their derivatives (TC-1 and TC-2 from CXCL-7). After activation by agonists (ADP and thrombin), platelets release these molecules exerting dual functions, i.e., antimicrobial and chemoattractant for immune cells.

Figure 4

Platelet immune and hemostatic functions through cationic host defense peptides (CHDPs). (a) Platelet CHDPs arise as part of the arsenal inherited by their precursor cells or from extracellular uptake from plasma. (b) Some CHDPs are stored within granules and are released upon recognizing activation-inducing components exposed during vascular damage (collagen, thrombin, and ADP) or by the presence of microbial components (lipopolysaccharide). Taken together, platelet CHDPs are capable of eliminating a great diversity of pathogens. (c) Platelets contain HBD1 in their cytoplasm, and the presence of permeabilizing agents on the bacterial membrane (e.g., α-toxin) induces its release. HBD1 released by platelets kills bacteria directly or through NETs induction. (d) CHDPs of platelet originated or produced by other cells increase platelet activation (increased CD62P, GPIIb/IIIa surface expression, or TSP-1 and CD40L secretion), particularly for LL-37, through recognizing FPR2 receptor. Human neutrophil peptide-1 (HNP-1), human beta defensin 1-3 (HBD1-3), adenosine diphosphate (ADP), protease-activated receptors-1, -4 (PAR-1, -4), thrombospondin (TSP-1).

Figure 5

Functions described and probably exerted by antimicrobial molecules present in human platelets. Platelet-derived kinocidins and CHDPs participate in various scenarios, such as the direct microorganism killing, platelet activation and aggregation, and immune cells chemotaxis. Nevertheless, new contexts for and participation of platelet-derived antimicrobial molecules should be extensively explored, e.g., immunomodulation, antiviral and anticancer activity, among a plethora of potential functions.