We show here that certain activators of the liposensor subclass of class II nuclear hormone receptors, in particular those for LXR, PPARα, and PPARβ/δ, improve multiple parameters of the AD-like dermatosis in a hapten-induced mouse model. A very recent study also showed that a PPARα activator prevented the emergence of inflammation in another murine model of AD34
. Since the present model recapitulates virtually all of the known clinical, structural, functional, lipid biochemical, and immunologic abnormalities of human AD19
, their efficacy suggests that these agents may hold promise for the treatment of human AD. Interestingly, not all of the activators were effective; i.e., neither the LXR activator, 22rOH-cholesterol, nor the PPARα activator, clofibrate, demonstrated benefits. The apparent lack of benefit of 22rOH-cholesterol could also be due to the fact that this naturally-occurring compound could be metabolized further into inactive species. Alternatively, at an applied dose of 10 mM, 22rOH cholesterol could act as a bulk lipid that destabilizes extracellular lamellar bilayers35
. Moreover, neither of the two PPARγ activators displayed broad efficacy, despite a recent report that a PPARγ activator, rosiglitazone, displays some anti-inflammatory activity in human AD36
. Moreover, it remains possible that PPARγ activators could be effective when administered systemically, rather than topically. Furthermore, it remains to be determined whether results from this AD mouse model, which may not be a strict analogue of human AD, necessarily will predict efficacy for human AD. For example, many cases of human AD are of different etiology (e.g., inherited filaggrin deficiency), and can be complicated by colonizing microbial pathogens, which further aggravate the barrier abnormality in human AD37
, but are not known to exacerbate dermatitis in the mouse analogues. Hence, empiric testing of individual activators of these receptors will be needed to determine whether the activators are delivered transdermally, and agents are of optimal benefit.
PPARs and LXR activators likely improve barrier function by at least two parallel mechanisms - stimulation of epidermal differentiation and lipid production [rev. in 15
]. Since increased epidermal lipid production likely generates additional endogenous activators of these nuclear hormone receptors, this process can be viewed as a type of feed-forward mechanism that coordinately regulates generation of both the corneocytes and the extracellular matrix of the SC.
According to the ‘outside-inside’ view of disease pathogenesis37, 38
, inherited abnormalities in proteins important for the barrier predispose to the development of AD. Conversely, normalization of barrier function would, in turn, reduce the two major drivers of inflammation in AD: 1) Cytokine generation, originating from perturbed corneocytes, as a signal that upregulates homeostatic repair mechanisms, should decline. Indeed, our results show that both IL-1α and TNFα levels decline after PPAR and LXR activator treatment; 2) while the second mechanism is self-evident, it has not yet been experimentally verified; i.e., improved permeability barrier function would simultaneously reduce the transdermal penetration of pro-inflammatory xenobiotes, including haptens and microbial pathogens. Of course, there is evidence in other cell types that certain PPARs, particularly PPARδ activators, exert anti-inflammatory effects on macrophages and T cells15
. Whether this mechanism was operative in these studies was not, however, assessed. Pertinently, both topical retinoids and 1,25 dihydroxyvitamin D3 analogues aggravate human AD (perhaps by activating epidermal pro-inflammatory cytokines39
, or by further aggravating the barrier abnormality). Notably, they also accentuate disease expression in the Ox-AD model (Hatano, Y. and Elias, P.M., unpublished observations). The lack of efficacy of retinoids and vitamin D analogues in human AD is readily explicable by a comparison of the divergent activities shown by synthetic retinoids, vitamin D analogues, and the PPAR/LXR on epidermal structure and function (Table 1S in the Online
). Notably, both retinoids and vitamin D analogues impair barrier function, and stimulate epidermal proliferation in vivo, while retinoids (but not vitamin D analogues) also impede epidermal differentiation. Furthermore, it should be noted that the predicted activity profile of PPAR/LXR (and retinoids/vitamin D analogues) will be dependent upon the expression levels of their respective receptors, as well as their heterodimerizing partner, RXR, which could independently influence ligand activity in AD.
A final key question remains: AD certainly is not the only dermatosis that is attributed to inherited mutations that alter barrier function. At least three other disorders (i.e., epidermolytic hyperkeratosis due to K1/K10 mutations; loricrin keratoderma; and transglutaminase 1-deficient lamellar ichthyosis) all display barrier abnormalities, but no known propensity to develop AD. Could the more coherent SC in these disorders restrict antigen access?
Since these studies demonstrate broad and potent anti-inflammatory properties in yet another mouse disease model, i.e., hapten-induced AD, the PPAR/LXR activators could be effective in a variety of other dermatologic settings. Yet, these studies did not examine all of the anti-inflammatory mechanisms by which these agents could work. While they could exert direct effects on leukocytes and macrophages, as has been shown for some of the liposensors agents in other clinical settings [cited in 15
], our studies suggest alternatively or additionally, that the liposensor activators reduce inflammation by first normalizing permeability barrier function. As a result of, or at least in parallel with a return of barrier function to normal, the amplitude of cytokine generation declined in response to treatment with the liposensor activators. Likely, the downstream signal cascade that follows cytokine production subsequently declines, which should, in turn, decrease the downstream signaling of chemokines and adhesion molecules that lead to inflammation (‘outside-inside’ paradigm for the pathogenesis of inflammatory dermatoses)1, 2, 4
. Since all of the liposensor activators (except PPARγ) improved barrier function in Ox-AD mice, normalization of barrier function alone could account for decreased inflammation by downregulation of the cytokine cascade, as has been shown for other approaches that correct barrier function followed by a decrease in cytokine signalling26, 40, 41
. If the principal anti-inflammatory mechanism is secondary to restored barrier function, then it is interesting to speculate whether topical therapy might be substantially more effective than systemic therapy with these same agents. Yet, reduction in inflammation also could improve barrier function34
, since a ‘vicious cycle’ is operative in the pathogenesis of AD38, 41, 42