Sheedy FJ, Grebe A, Rayner KJ, Kalantari P, Ramkhelawon B, Carpenter SB, Becker CE, Ediriweera HN, Mullick AE, Golenbock DT, Stuart LM, Latz E, Fitzgerald KA, Moore KJ. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol. 2013 Aug;14(8):812-20. PubMed.
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Charité Universitaetsmedizin Berlin
The identification of CD36 as a key upstream regulator of NLRP3 activation by endogenous, potentially dangerous ligands in three major diseases—namely atherosclerosis, Alzheimer’s disease (AD), and type 2 diabetes—is an important and encouraging finding for many reasons. It elucidates an important innate immune mechanism to contain amyloidosis. Due to the fact that CD36 does not compromise the inflammasome activity required for host defense against pathogens, it provides an attractive and smart target for therapeutic intervention in amyloid-prone diseases. The work also highlights the potential of modulating innate immunity in proteopathic (brain) diseases by identifying CD36 as the common molecular event, even though the initiating pathology in these diseases may differ considerably.
While CD36 is already known to mediate microglial and macrophage responses to Aβ, implying that it plays a key role in the proinflammatory events associated with AD (El Khoury et al., 2013), the finding by Sheedy et al. suggests it may be feasible to therapeutically target NALP3 in AD (Heneka et al., 2013).
However, it was also shown that the peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone induced Aβ clearance in AD mice by stimulating microglial Aβ phagocytosis in a CD36-mediated manner (Yamanaka et al., 2013).
Therefore, downregulating CD36 may not only reduce inflammation but may also diminish clearance of Aβ. In this context, the finding by Hickman et al., 2008 describing a substantial decrease in expression of the Aβ-binding scavenger receptors scavenger receptor A, CD36, and RAGE in microglia from old Aβ-laden PS1-APP mice, as well as the increase in microglial CD36 expression in NLRP3-deficient AD mice (Heneka et al.) need to be considered. It will be important to assess AD pathology beyond in-vitro assays in a preclinical in-vivo setting using AD mouse models crossed to CD36-deficient mice. This will also allow us to examine whether not only peripheral macrophages, but also intrinsic microglial functions are changed in the experimental paradigms presented by Moore and colleagues.
References:
El Khoury JB, Moore KJ, Means TK, Leung J, Terada K, Toft M, Freeman MW, Luster AD. CD36 mediates the innate host response to beta-amyloid. J Exp Med. 2003 Jun 16;197(12):1657-66. PubMed.
Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature. 2013 Jan 31;493(7434):674-8. Epub 2012 Dec 19 PubMed.
Hickman SE, Allison EK, El Khoury J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci. 2008 Aug 13;28(33):8354-60. PubMed.
Yamanaka M, Ishikawa T, Griep A, Axt D, Kummer MP, Heneka MT. PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J Neurosci. 2012 Nov 28;32(48):17321-31. PubMed.
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