FcεRI and FcγRIII/CD16 Differentially Regulate Atopic Dermatitis in Mice

Abstract

The high-affinity IgE receptor FcεRI and, in some models, the low-affinity IgG receptor FcγRIII/CD16 play an essential role in allergic diseases. In human skin, they are present on APCs and effector cells recruited into the inflamed dermis. FcRγ is a subunit shared, among other FcRs, by FcεRI and CD16 and is essential to their assembly and signal transduction. Using an experimental model reproducing some features of human atopic dermatitis and specific FcR-deficient mice, we have herein delineated the respective contribution of FcεRI and FcγRIII/CD16 to the pathology. We demonstrate that symptoms of atopic dermatitis are completely absent in FcRγ-deficient animals but only partially inhibited in either FcεRI- or FcγRIII/CD16-deficient animals. Absence or attenuation of the pathology is correlated to increased skin expression of regulatory IL-10 and Foxp3. While FcεRI controls both Th1 and Th2 skin response, mast cell recruitment into draining lymph nodes and IgE production, CD16 regulates only Th2 skin response, as well as T cell proliferation and IgG1 production. This isotype-specific regulation by the cognate FcR is associated to a differential regulation of IL-4 and IL-21 expression in the draining lymph nodes. FcεRI and CD16 thus contribute to atopic dermatitis but differentially regulate immune responses associated with the disease. Targeting both IgE/FcεRI and IgG/CD16 interactions might represent an efficient therapeutic strategy for allergic diseases.

Mast cells in atopic dermatitis

“…However, careful mast cell-reconstitution experiments have not been performed in either study. Interestingly, a recent study showed that FcεRI and FcRγ are involved in an EC OVA sensitization model [81]. However, what cell type is involved was not investigated in this study.…”

Th2 Cytokines and Atopic Dermatitis

“…As discussed earlier, not all patients with AD show elevated IgE levels. In a murine AD model induced by epicutaneous exposure to ovalbumin, Abboud et al demonstrated that IgE signaling through the FcεRI receptor partially contributed to the AD phenotype, but IgG signaling through the FcγRIII/CD16 low affinity receptor also contributed significantly to the phenotype [50]. In the absence of FcεRI, there was a partial decrease in skin thickening and cellular inflammation, along with attenuated expression of Th1, Th2 and Th17 cytokines.…”

Mast Cells Are Dispensable in a Genetic Mouse Model of Chronic Dermatitis

“…37 Consistent with this finding, the AD-like symptoms were only mildly reduced in FcεRI-deficient mice. 38 On the other hand, skin inflammation induced by epicutaneous sensitization with cedar pollen antigens was abolished in Kit W/W-v and Kit Sl/Sl-d mice. 39 Similarly, the AD-like symptoms induced by epicutaneous application of Dermatophagoides farinae extract and staphylococcal enterotoxin B were strongly reduced in Kit W-sh/W-sh40 and also in Cpa3-Cre transgenic, Mcl-1 fl/fl mice, 41 which lack mast cells and basophils and have macrocytic anemia and neutrophilia.…”