The role of platelets in immune-mediated inflammatory diseases

Abstract

Immune-mediated inflammatory diseases (IMIDs) are characterized by excessive and uncontrolled inflammation and thrombosis, both of which are responsible for organ damage, morbidity and death. Platelets have long been known for their role in primary haemostasis, but they are now also considered to be components of the immune system and to have a central role in the pathogenesis of IMIDs. In patients with IMIDs, platelets are activated by disease-specific factors, and their activation often reflects disease activity. Here we summarize the evidence showing that activated platelets have an active role in the pathogenesis and the progression of IMIDs. Activated platelets produce soluble factors and directly interact with immune cells, thereby promoting an inflammatory phenotype. Furthermore, platelets participate in tissue injury and promote abnormal tissue healing, leading to fibrosis. Targeting platelet activation and targeting the interaction of platelets with the immune system are novel and promising therapeutic strategies in IMIDs.

Fig. 1. Effects of platelet activation.

a, Resting platelets express platelet-specific markers such as the glycoproteins GPIIb/IIIa, GPIb and GPVI. Platelets also express Fcγ receptor (FcγR), which enables them to scavenge circulating immune complexes. Resting platelets may inhibit CD8⁺ T cells by the expression of MHC class I molecules in the absence of co-stimulatory molecules, as well as by expressing the ectonucleosidase CD73, which catalyses the production of anti-inflammatory adenosine from adenosine monophosphate (AMP). b, Activated platelets release cytokines such as IL-1, and molecules such as soluble P-selectin (sP-selectin), soluble CD40 ligand (sCD40L) and serotonin. They also release damage-associated molecular patterns (DAMPs), such as calprotectin and high mobility group box 1 (HMGB1), and extrude mitochondria and mitochondrial DNA (mtDNA) into the extracellular milieu. Activated platelets relocalize to their surface glycoproteins such as P-selectin and CD40L that are initially present in cytoplasmic granules, which promotes interaction with immune cells. Platelet antigens and scavenged immune complexes are captured by antigen-presenting cells (APCs) for processing and immune presentation. Furthermore, platelets express MHC class I molecules together with the co-stimulatory molecule CD86, and may directly present antigen to CD8⁺ T cells and promote their activation. Finally, activated platelets produce platelet-derived extracellular vesicles that contain platelet-derived molecules such as P-selectin, CD40L, HMGB1 and IL-1. TCR, T cell receptor.

Fig. 2. Activated platelets interact with and activate innate and adaptive immune cells.

Activated platelets and platelet-derived extracellular vesicles physically interact with immune cells and stimulate an inflammatory response. a, Innate immunity. Platelets aggregate with plasmacytoid dendritic cells (pDCs) through CD40 ligand (CD40L)–CD40 interactions and stimulate interferon-α (IFNα) production in response to circulating immune complexes. Platelets also interact with monocytes and neutrophils through the P-selectin–P-selectin glycoprotein ligand 1 (PSGL1) axis, leading to the maturation of monocytes to antigen-presenting cells (APCs) and the priming of neutrophils. Platelets release mitochondria and mitochondrial DNA (mtDNA), which induce neutrophil activation and the production of neutrophil extracellular traps (NETosis). This leads to the release of autoantigens that are processed by APCs and presented to lymphocytes. b, Adaptive immunity. Activated platelets express membrane CD40L and soluble CD40L (sCD40L), which stimulate B cell responses and the production of autoantibodies. P-selectin-positive platelets and platelet-derived extracellular vesicles interact with regulatory T cells (T_reg cells), leading to FOXP3 downregulation and T_reg cell dysfunction. BCR, B cell receptor; FcγR, Fcγ receptor; sP-selectin, soluble P-selectin; TCR, T cell receptor.

Fig. 3. Role of the P-selectin–PSGL1 axis in immune-mediated inflammatory disease.

Inflammatory disease activity promotes platelet activation through increased levels of immune complexes, autoantibodies and damage-associated molecular patterns. Upon activation, platelets express P-selectin on their surface, release soluble P-selectin and produce P-selectin-positive platelet-derived extracellular vesicles. P-selectin subsequently interacts with immune cells through binding to its ligand P-selectin glycoprotein ligand 1 (PSGL1). In regulatory T (T_reg) cells and T follicular regulatory (T_FR) cells, P-selectin–PSGL1 interaction induces FOXP3 downregulation and cell dysfunction, leading to immune dysregulation, production of autoantibodies and further platelet activation. In neutrophils, P-selectin–PSGL1 interaction promotes the production of neutrophil extracellular traps (NETosis), leading to the release of autoantigens that are processed by antigen-presenting cells (APCs). P-selectin promotes the differentiation of monocytes to pro-inflammatory APCs expressing high levels of MHC class II, CD80 and CD86 to efficiently prime and co-stimulate T cells. BCR, B cell receptor; CD40L, CD40 ligand; TCR, T cell receptor; T_FH, T follicular helper.

Fig. 4. Potential therapeutic strategies to target platelets in immune-mediated inflammatory disease.

Two strategies may be used to target platelets in immune-mediated inflammatory disease: inhibiting platelet activation or inhibiting the interaction between platelets and immune cells. a, Platelet activation can be inhibited by blocking agonist engagement (for example, blocking adenosine diphosphate (ADP) binding to its receptor P2Y₁₂ with clopidogrel), inhibiting platelet cyclooxygenase (COX) activity using aspirin, inhibiting Toll-like receptor 7 (TLR7) activation using hydroxychloroquine, inhibiting Fcγ receptor (FcγR) engagement or activation using high-dose intravenous immunoglobulin (IVIg), inhibiting the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome with colchicine and inhibiting intracellular signalling (for example, targeting AMP-activated protein kinase (AMPK) with metformin, spleen tyrosine kinase (SYK) with fostamatinib or Bruton’s tyrosine kinase (BTK) with a specific inhibitor). b, Platelet–immune cell interactions can be inhibited by targeting ligand–receptor pairs that mediate these interactions. For example, antibody to P-selectin prevents P-selectin binding to P-selectin glycoprotein ligand 1 (PSGL1) on neutrophils and other immune cells, and antibodies targeting CD40 or CD40 ligand (CD40L) prevent interaction with B cells. Fab, antigen-binding fragment.