Aryl Hydrocarbon Receptor senses in[toxic]ated skin environment

Aryl Hydrocarbon Receptor (AhR) sense the presence of xenobiotics (e.g. antibiotics) or toxic environmental pollutants (e.g. dioxin). This process induces activation of liver enzymes, like CYP1A1, necessary for toxin deactivation. AhR's endogenous ligands are dietary-derived indoles and flavonoids. In addition, some high affinity endogenous AhR ligands, like FICZ, are derived from tryptophan metabolism upon UV or visible light exposure.

Many immune-related inflammatory disorders, like allergy, asthma or eczema are thought be exaggerated by environmental pollutants.

I would like to review two recent papers (second review is coming in few days) that address the role of AhR in tissue inflammatory response.

The first paper was published in Immunity and came from Brigitta Stockinger' lab (1).

Her lab is well known for their pioneering work in Th17 subset biology. I actually remember that it was in the summer of 2006 when our Lab Chief came from one of the conference and mentioned that Brigitta Stockinger's lab has identified new T helper subset that required IL-6 and TGF-beta. It was complete unorthodox idea then. That original paper itself was published a little bit later in Immunity.

In this new immunity paper, her lab examined the role of AhR in imiquimod-induced psoriasiform skin inflammation (if interested, I have already reviewed earlier paper from von Andrian's lab about imiquimod-induced psoriasiform skin inflammation).

Imiquimod is a anti-viral topical medicine. It activates TLR7 and also activates, indirectly, nociceptors and IL-23-IL-17 axis.

First, the authors examined effect of AhR agonist, FICZ, on psoriasis-related gene (psoriasis transcriptome) expression using clinical skin biopsies. 70% of psoriasis-related genes (e.g. IFIT1) were reduced after treatment of lesional skin biopsies with FICZ.

To study AhR effect on psoriasiform skin inflammation, the authors used AhR-deficient mouse model. While untreated skins from both AhR +/+ and AhR -/- mice were similar, 5-day application of imiquimod induced greater inflammation and skin thickening in AhR -/- mice. This exaggerated skin inflammatory response was reduced with FICZ. The authors did not show data if any off-target effect exist with FICZ (e.g. treatment of AhR -/- mice with FICZ after imiquimod application).

Next, the authors conducted series of experiment to determine which cell subset required AhR expression to recapitulate clinical observation of AhR -/- mice. There was no difference in skin inflammation when AhR was specifically deleted in CD11c+ cells (Ahr fl/- CD11c-cre mice). Also, Specific deletion of AhR in T and B cells (Ahr fl/- RAG1-cre mice) did not recapitulate clinical observation seen in AhR -/- mice after imiquimod application.

However, bone marrow chimeras in which nonhematopoietic cells were of AhR -/- phenotype but bone marrow cells of wild type could recapitulate total AhR deficiency, but not other way around. This indicated that absence of AhR response in the nonhematopoietic cell subsets contributed to observed exaggerated skin inflammation in AhR-deficient mice after imiquimod application.

The authors further showed that AhR -/- skin cells (keratinocytes) showed hyper responsiveness (greater expression of cxcl1, csf2, csf3) to condition medium derived from imiquimod treated skin samples. This exaggerated response of AhR -/- keratinocytes were primarily driven by IL-1beta, since recombinant IL-1beta could replace condition medium for this effect and neutralization of IL-1beta abrogated keratinocytes hyper response to imiquimod treated skin condition medium.

In summary, this paper showed that AhR expression in keratinocytes is required to dampen skin inflammatory response to IL-1beta during psoriasiform skin reaction. The source of this IL-1beta is not shown here but presumably is derived from hematopoietic cells, like dendritic cells, since its production requires inflammasome activation. While, the authors did not identify the ligands that activate AhR in keratinocytes in imiquimod-induced psoriasiform skin, the fact that sunlight and two light-sensitive vitamins D and A derived medicine (calcipotriol, isotretinoin) has been shown to be effective in psoriasis treatment indicate that AhR ligands represent prospective medical targets.

David

Type I IFN signaling makes T cells perforin-proof

   Upon antigen encounter, T cells become activated, proliferate and differentiate into effector or memory population. Cytokines play a fundamental role in these processes. For example, IFN receptor deficient CD8 T cells do not survive after viral infection. It is thought that type I IFN signaling in T cells imprint survival and effector differentiation quality.

   However, two new studies published in Immunity, provided an alternative and surprising explanation for the beneficial effect of type I IFN signaling in T cells. I found the results of these studies to be of sufficient significance to qualify for my review.

   One paper has two two co-first authors, Heifeng C. Xu and Melanie Grusdat (1).

   In this paper, first set of experiments showed that while in vitro wild-type (WT) and IFN-alpha receptor deficient CD8 T cells behave the same way, in vivo IFN-alpha receptor deficient CD8 T cells (unlike WT CD8 T cells) quickly disappear upon transfer into virus infected host. The same effect was seen with IFN-alpha receptor deficient CD4 T cells (smarta T cells).

   Interestingly, adoptive transfer of IFN-alpha receptor deficient CD8 T cells into virus infected host, depleted of NK cells, restored IFN-alpha receptor deficient T cells numbers. The similar effect was seen in virus infected hosts genetically deficient of NK cells (Nfil-deficient mice). These results indicated that NK cells may specifically target activated IFN-alpha receptor deficient T cells for elimination.

      In vitro experiment showed that type I IFN signaling induces MHC class I and non-classical MHC Ib (Qa-1b) molecules on the surface of T cells. These molecules were known to inhibit NK cell activity.

    Accordingly, in vitro NK cells selectively eliminated IFN-alpha receptor deficient CD8 T cells compared WT CD8 T cells via perforin-mediated pathway. Finally, adoptive transfer of IFN-alpha receptor deficient CD8 T cells into virus infected perforin-deficient hosts restored IFN-alpha receptor deficient T cells numbers and no further increase was detected after NK cell depletion.

   In sum, these results indicate that signaling through IFN-alpha receptor in T cells is necessary to prevent early elimination of T cells by primed NK cells after virus infection.

    Second paper is from Oxenius lab. The first author is Josh Crouse. It is more detailed study but with the same conclusion (2).

  This second group also observed that NK cell depletion with anti-NK1.1 or anti-Asialo GM1 antibody restored expansion of adoptively transferred IFN-alpha receptor deficient T cells (both LCMV specific P14 CD8 T cells and smarta CD4 T cells). Interestingly, only activated but not naïve T cells became sensitive to NK cells. This group also found that adoptive transfer of IFN-alpha receptor deficient P14 CD8 T cells or smarta CD4 T cells into LCMV virus infected perforin-deficient hosts restored IFN-alpha receptor deficient P14 CD8 and smarta CD4 T cells numbers and no further increase was detected after NK cell depletion. Finally, the authors found that NK cells preferentially killed IFN-alpha receptor deficient T cells in vivo and in vitro through NCR1-mediated pathway.

    In summary, these two studies showed that during acute viral infection, antigen activated T cells become sensitized to NK cell killing in absence of type I IFN signaling. Mechanistically, in absence of IFN signaling in T cells, T cells upregulate activating NCR1 ligand. Since without type I IFN signaling, inhibitory ligands like MHC class I, are not upregulated, this leads to T cell sensitization to NK cell killing via perforin.

     In my view, one important discussion missing from both studies is the role of NK cells or CD8 T cells in acute LCMV infection. Can LCMV infect type I IFN receptor deficient T cells? Why are NK cells targeting T cells at such a early stage of infection (day 3-7)? Is NK cell depletion beneficial for the virus (LCMV)-infected hosts?

David

Chronic infection and the origin of adaptive immune system

If you are interested in immunological modeling or theories (which is my special interest), this hypothetical article is for you. I think it has some unique ideas.

I would like to point out that more recent studies of jawless vertebrate immune system reveal that they also contain adaptive-like immune system, probably as diverse as of jawed vertebrates (1).

  

Med Hypotheses. 2010 Aug;75(2):241-3.

David Usharauli

Abstract

It has been speculated that the rise of the adaptive immune system in jawed vertebrates some 400 million years ago gave them a superior protection to detect and defend against pathogens that became more elusive and/or virulent to the host that had only innate immune system. 

First, this line of thought implies that adaptive immune system was a new, more sophisticated layer of host defense that operated independently of the innate immune system. 

Second, the natural consequence of this scenario would be that pathogens would have exercised so strong an evolutionary pressure that eventually no host could have afforded not to have an adaptive immune system. Neither of these arguments is supported by the facts. 

First, new experimental evidence has firmly established that operation of adaptive immune system is critically dependent on the ability of the innate immune system to detect invader-pathogens and second, the absolute majority of animal kingdom survives just fine with only an innate immune system. Thus, these data raise the dilemma: If innate immune system was sufficient to detect and protect against pathogens, why then did adaptive immune system develop in the first place? 

In contrast to the innate immune system, the adaptive immune system has one important advantage, precision. By precision I mean the ability of the defense system to detect and remove the target, for example, infected cells, without causing unwanted bystander damage of surrounding tissue. 

While the target precision per se is not important for short-term immune response, it becomes a critical factor when the immune response is long-lasting, as during chronic infection. In this paper I would like to propose new, "toxic index" hypothesis where I argue that the need to reduce the collateral damage to the tissue during chronic infection(s) was the evolutionary pressure that led to the development of the adaptive immune system.

for whole article please see

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2897935/

David