Characterization of Platelet–Monocyte Complexes in HIV-1–Infected Individuals: Possible Role in HIV-Associated Neuroinflammation

Abstract

HIV-1-associated neuroinflammation persists even with effective combined anti-retroviral therapy (cART), and is associated with the presence of activated monocytes/macrophages within the CNS. In order to infiltrate the CNS, monocytes transmigrate across the selectively permeable blood brain barrier (BBB), which is compromised during HIV infection. Interestingly, platelet-derived excess soluble CD40L (sCD40L) found in the plasma and cerebrospinal fluid (CSF) of HIV-1 infected individuals with cognitive impairment has previously been implicated in increased BBB permeability. Here we show that sCD40L also promotes the formation of complexes between inflammatory monocytes and activated platelets (PMCs), which are detected by flow cytometry as monocytes that express excess of CD61, a platelet marker and that these complexes are increased in individuals with HIV infection. PMCs exhibit an enhanced ability to adhere to human brain microvascular endothelial cells as compared to monocytes alone and migrate across transendothelial barrier. These complexes can be found marginalized in the lumen of post-capillary venules in post-mortem brain tissue derived from cases of HIV-1-associated encephalitis (HIV-E). The extravasation of monocytes across the brain endothelium may exacerbate neuroinflammation, indicating that enhancing this event via platelet interaction may be a contributing factor in the development of cognitive impairment. Thus, dampening platelet activation, and in turn PMC formation, with anti-platelet agents may prove beneficial in developing adjunctive therapies for use in combination with cART in an effort to reduce HIV-1-associated neurological deficit

Histamine deficiency facilitates coronary microthrombosis after myocardial infarction by increasing neutrophil‐platelet interactions

“…Activated platelets interact with monocytes directly, leading to the increased expression of CD40, CD11b and PSGL‐1 on monocytes. This results in the formation of monocyte‐platelet aggregates in the inflammatory area and promotes monocyte recruitment . Moreover, histamine deficiency impairs macrophage infiltration and suppresses the healing process post‐AMI, which interferences with the clearance of debris and tissue repair .…”

Platelet Interaction with Innate Immune Cells

“…Activated platelets further facilitate this process. Platelets directly interact with monocytes, leading to enhanced expression of CD40, PSGL-1, CD11b and CCR2 on the monocyte surface [21,22]. This, in turn, enhances platelet-monocyte aggregate formation and recruitment of further monocytes to the endothelium [21,[23][24][25].…”

“…Platelets directly interact with monocytes, leading to enhanced expression of CD40, PSGL-1, CD11b and CCR2 on the monocyte surface [21,22]. This, in turn, enhances platelet-monocyte aggregate formation and recruitment of further monocytes to the endothelium [21,[23][24][25]. The initial interaction between platelets and monocytes is mediated by CD62P-PSGL-1 binding [1], which is further stabilised by CD40L-MAC-1, GPVI-CD147 or via interaction of intercellular adhesion molecule 1 (ICAM-1) with plateletbound fibrinogen [1,25].…”

Renal Denervation Reduces Monocyte Activation and Monocyte–Platelet Aggregate Formation

“…Here, a protocol previously used in clinical studies was applied. [14][15][16] Monocytes were identified using the surface marker CD14 and platelets using the integrin subunit CD61, which is highly expressed on platelets, but not to a significant level, in flow cytometry detectable level on monocytes (β3; Figure 3C). After RDN, basal MPAs significantly decreased at 3 months (P<0.01; Figure 3C) after RDN, while only a numeric but statistically nonsignificant reduction was observed at the 6-month time point (P=0.1387; Figure 3C).…”