Protecting Skin Cells from Apoptosis
The TNF-α pathway, via mechanisms that are unclear, has been shown to regulate skin homeostasis and inflammation. Studies investigating the regulation of TNF-α signaling by linear ubiquitin chain assembly complex (LUBAC)-mediated M1 ubiquitination in skin inflammation have produced contrasting results, primarily because deficiency in the LUBAC catalytic subunit RNF31 is embryonically lethal in mice. To that end, Tang et al. (p. 4117) generated epidermis-specific RNF31 knockout (RNF31E-KO) mice, which died 4–6 d after birth from severe skin inflammation. Although skin structure in these mice appears normal at postnatal day 1, the authors observed severe hyperplasia and decreased keratinocyte differentiation at postnatal days 3 and 5. RNA sequencing and RT-PCR of total skin tissues from 3-d-old RNF31E-KO and wild-type (WT) control mice showed upregulation of genes involved in inflammation, including chemokine, cytokine–cytokine receptor, and NF-κB signaling pathways in the former mice. Consistent with these observations, macrophages, dendritic cells, and neutrophils were significantly increased in the epidermis and dermis of RNF31E-KO mice. Mechanistically, loss of RNF31 in the skin significantly increased keratinocyte apoptosis in 3-d-old mice. RNF31 deficiency can trigger apoptosis prior to inflammation, as 1-d-old mice, whose skin did not show any obvious signs of inflammation, had fewer surviving keratinocytes than did WT controls. Interestingly, TNF receptor 1 (TNFR1) deficiency in RNF31E-KO mice prolonged their survival, rescued defects in skin proliferation and differentiation, and significantly decreased skin inflammation. Collectively, these results demonstrate that RNF31 plays a role in skin homeostasis by protecting keratinocytes from TNF-α–mediated apoptosis and suggest that LUBAC components may be potential targets to treat inflammatory skin conditions.
Modeling Myeloid Cell Movements in Monkeys
To date, studies defining the kinetics of myeloid cell movement to maintain homeostasis in humans are technologically constrained. Because translation of results from rodents to humans is confounded by a number of variables, nonhuman primates are a viable model as they are physiologically similar to humans and yet allow effective in vivo cell labeling and repeated sampling. In this issue, He et al. (p. 4059) assessed circulating myeloid cell populations of 5- to 10-y-old rhesus macaques at different time points following systemic BrdU administration. Myeloid cells exhibited distinct kinetics in the blood under homeostatic conditions; whereas BrdU-labeled classical monocytes appeared in the blood as soon as 1 d after BrdU administration, labeled basophils and neutrophils were observed in the blood 2 and 4 d after BrdU administration, respectively. Thus, basophils and neutrophils appeared to require a 2–4-d maturation period in the bone marrow before release into the circulation. The authors then developed and applied a mathematical model to fit the BrdU kinetics data to estimate the half-life and daily production of each distinct myeloid cell population in the blood. Neutrophils and basophils had similar half-lives, at 1.6 and 1.7 d, respectively, which were slightly longer than the 1-d half-life of classical monocytes. Neutrophils and classical monocytes were produced in large quantities daily (∼ 1.42 × 109 and 3.09 × 108 cells/l/d respectively), whereas basophil daily production was relatively moderate (5.89 × 106 cells/l/d). In addition, the authors examined a group of rhesus macaques of both sexes between 3 and 19 y of age to determine the effect of aging on myeloid cell kinetics. Daily production of neutrophils and basophils significantly diminished with increased age, but the half-life of these granulocytes remained constant. In contrast, daily production of classical monocytes remained stable with age, but their half-life significantly decreased with age. Collectively, these data provide a model to understand the dynamics of myeloid cells in humans during homeostasis and how age may impact these properties.
Delineating the Role of Somatic Hypermutation in Lupus
Systemic lupus erythematosus (SLE) is an autoimmune disease associated with lupus nephritis, which is characterized by accumulation of autoreactive IgG and C3 in the kidney and subsequent impairment of kidney function. Activation-induced deaminase (AID) is involved in somatic hypermutation (SHM) and class-switch recombination (CSR), both of which have been shown to contribute to SLE pathology. Given that the relative contributions of SHM and CSR in SLE are unknown, Hao et al. (p. 3905) generated a mouse model on the MRL/lpr background, in which SHM is specifically abolished due to a mutation in AID (AIDG23S), whereas CSR is largely unaffected. In AID−/− MRL/lpr mice, which are deficient in both CSR and SHM, total IgG and anti-dsDNA IgG were almost completely eliminated, whereas anti-dsDNA IgG, but not total IgG, was significantly decreased in AIDG23S relative to AID+/+ MRL/lpr mice. Similarly, the levels of anti-nuclear Abs—a hallmark of SLE—were lower in AIDG23S MRL/lpr mice than in AID+/+ MRL/lpr mice. These results indicate that SHM deficiency prevented the accumulation of SLE-associated autoreactive IgG. Compared with AID+/+ MRL/lpr mice, the deposition of C3 and IgG was diminished in the glomeruli of AIDG23S (and AID−/−) MRL/lpr mice, suggesting that SHM is required for SLE-associated accumulation of IgG and C3 in glomeruli. Finally, loss of SHM alleviated histopathological alterations in the kidney, resulting in decreased inflammatory cell infiltration, improved renal function, and prolonged lifespan of mice lacking SHM. These studies dissect the individual contribution of SHM and CSR to SLE pathogenesis and demonstrate that SHM is essential for the development of SLE, highlighting the importance of delineating these mechanisms to allow for precise control of AID as a potential therapeutic strategy.
IL-10 and Immunosuppression in CLL
Chronic lymphocytic leukemia (CLL) cells produce IL-10, an immunosuppressive cytokine that can inhibit T cell responses by both direct and indirect means. However, the role of IL-10 in CLL-associated immunosuppression is unknown. Thus, Alhakeem et al. (p. 4180) examined the role of CLL-derived IL-10 in the suppression of host antitumor immunity. Eμ-TCL1 CD5+CD19+ CLL cells constitutively secrete IL-10, but in vitro neutralization of IL-10 using anti–IL-10 or anti–IL-10 receptor (IL-10R) Abs did not affect their survival, suggesting that IL-10 may influence CLL cell growth indirectly. Injected CLL cells grew at a slower rate in IL-10R−/− mice than in wild type (WT) mice, and CD8+ T cells from IL-10R−/− recipients proliferated better and produced more IFN-γ than those from WT mice. Next, the authors used NSG mice injected with CLL cells and purified CD8+ T cells from WT or IL-10R−/− mice primed with CLL. CD8+ T cells from IL-10R−/− mice delayed CLL growth in NSG hosts, relative to CD8+ T cells from WT mice. Activation of BCR signaling and binding to the IL-10 promoter by Sp1, a transcription factor known to regulate IL-10 gene expression, induced IL-10 production by CLL cells. Sp1 mRNA and protein levels were reduced in the presence of an ERK1/2 inhibitor, revealing that IL-10 production by CLL cells is regulated by ERK1/2-dependent activation of Sp1. Similarly, inhibition of BCR signaling in human CLL cells reduced ERK1/2 activation and Sp1 and IL-10 expression. These studies identify the signaling pathways involved in IL-10 production by CLL cells and demonstrate a link between CLL-derived IL-10 and impaired T cell responses in CLL. Therefore, inhibition of IL-10 in a combination setting, such as with BCR signaling inhibitors, has the potential to offer therapeutic benefit in the treatment of CLL.
- Copyright © 2018 by The American Association of Immunologists, Inc.
