Excess Soluble CD40L Contributes to Blood Brain Barrier Permeability In Vivo: Implications for HIV-Associated Neurocognitive Disorders

Abstract

Despite the use of anti-retroviral therapies, a majority of HIV-infected individuals still develop HIV-Associated Neurocognitive Disorders (HAND), indicating that host inflammatory mediators, in addition to viral proteins, may be contributing to these disorders. Consistently, we have previously shown that levels of the inflammatory mediator soluble CD40L (sCD40L) are elevated in the circulation of HIV-infected, cognitively impaired individuals as compared to their infected, non-impaired counterparts. Recent studies from our group suggest a role for the CD40/CD40L dyad in blood brain barrier (BBB) permeability and interestingly, sCD40L is thought to regulate BBB permeability in other inflammatory disorders of the CNS. Using complementary multiphoton microscopy and quantitative analyses in wild-type and CD40L deficient mice, we now reveal that the HIV transactivator of transcription (Tat) can induce BBB permeability in a CD40L-dependent manner. This permeability of the BBB was found to be the result of aberrant platelet activation induced by Tat, since depletion of platelets prior to treatment reversed Tat-induced BBB permeability. Furthermore, Tat treatment led to an increase in granulocyte antigen 1 (Gr1) positive monocytes, indicating an expansion of the inflammatory subset of cells in these mice, which were found to adhere more readily to the brain microvasculature in Tat treated animals. Exploring the mechanisms by which the BBB becomes compromised during HIV infection has the potential to reveal novel therapeutic targets, thereby aiding in the development of adjunct therapies for the management of HAND, which are currently lacking.

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

“…Infection, as well as cognitive impairment during infection, is associated with an increase in plasma levels of soluble CD40L (sCD40L) (24), for which platelets are the major source (25). Consistent with this notion, recent reports from our group indicate that excess sCD40L contributes to blood brain barrier (BBB) permeability in the context of HIV (26), and that PMCs are elevated in individuals with HIV infection in spite of suppressive combined antiretroviral therapy (cART) (21). Collectively, these findings underscore the importance of PMCs in the pathogenesis of HIV-associated illnesses, and led us to the underlying hypothesis that during HIV infection, the increase in platelet activation and subsequent release of sCD40L promote the formation of PMCs, which in turn have a higher propensity to cross the blood brain barrier (BBB), thereby exacerbating HIV-associated neuroinflammation.…”

“…Ten to twelve-week old WT mice (n=6 for each group) were injected retro-orbitally with recombinant mouse sCD40L (rmsCD40L; 0.2 μg/g body weight) that had been resuspended in saline, as previously described (26). Two hours post-injection, whole blood was obtained via cardiac exsanguination and used for detection of PMCs.…”

Soluble CD40 Iigand and Oxidative Response Are Reciprocally Stimulated during Shiga Toxin-Associated Hemolytic Uremic Syndrome

“…The sCD40L plasmatic values showed by HUS patients were similar to those reported in other pathological conditions such as cardiovascular diseases, diabetes, HIV infection or smokers [41,[45][46][47][48][49] and it can be considered as a marker of thrombotic risk [26]. Therefore, and based on the present results, we propose that quantification of sCD40L in plasma could be used as a surrogate and early marker of microvascular dysfunction and/or platelet activation in Stx-associated diarrheas.…”

The physiology of blood platelets and changes of their biological activities in multiple sclerosis

“…Soluble form (sCD40L) is released from activated platelets and platelets release approximately 95% of all sCD40L found in plasma (Saluk-Juszczak and Królewska 2010). Excess sCD40L contributes to BBB permeability and is thought to regulate permeability in the inflammatory disorders of the CNS (Davidson et al 2012). PSGL-1, implicating platelets and can induce maturation and activation of dendritic cells.…”