IL-36 Promotes Myeloid Cell Infiltration, Activation, and Inflammatory Activity in Skin

Abstract

The IL-1 family members IL-36α (IL-1F6), IL-36β (IL-1F8) and IL-36γ (IL-1F9) and the receptor antagonist IL-36Ra (IL-1F5) constitute a novel signaling system that is poorly understood. We now show that these cytokines have profound effects on the skin immune system. Treatment of human keratinocytes with IL-36 cytokines significantly increased the expression of CXCL1, CXCL8, CCL3, CCL5, and CCL20, potent chemotactic agents for activated leukocytes, and IL-36α injected intradermally resulted in chemokine expression, leukocyte infiltration and acanthosis of mouse skin. Blood monocytes, myeloid dendritic cells (DC) and monocyte-derived DC (MO-DC) expressed IL-36R and responded to IL-36. In contrast, no direct effects of IL-36 on resting or activated human CD4+ or CD8+ T cells, or blood neutrophils, could be demonstrated. Monocytes expressed IL-1A, IL-1B and IL-6 mRNA and IL-1β and IL-6 protein and mDC upregulated surface expression of CD83, CD86 and HLADR and secretion of IL-1β and IL-6 after treatment with IL-36. Furthermore, IL-36α-treated MO-DC enhanced allogeneic CD4+ T cell proliferation, demonstrating that IL-36 can stimulate the maturation and function of DC and drive T cell proliferation. These data indicate that IL-36 cytokines actively propagate skin inflammation via the activation of keratinocytes, antigen presenting cells and, indirectly, T cells.

IL-36 receptor is expressed by human blood and intestinal T lymphocytes and is dose–dependently activated via IL-36β and induces CD4+ lymphocyte proliferation

“…In mice IL-36R has been reported to be expressed by splenic CD4+ T lymphocytes but not by CD8+ T lymphocytes or B lymphocytes [2]. Our study also differs from that of Foster et al, [14] which reports a lack of expression of IL-36R in human lymphocytes. It is possible that that some anomalies have arisen due to differences in this study and ours.…”

Autocrine and Paracrine Regulation of Keratinocyte Proliferation through a Novel Nrf2–IL-36γ Pathway

“…The potent proinflammatory activity of IL-36 cytokines also provides a possible explanation for the increased proliferation of keratinocytes that occurs in response to these cytokines in vivo (30,32,35), because immune cells produce various keratinocyte mitogens (36). In addition, we show in this article that IL-36g directly stimulates keratinocyte proliferation.…”

“…IL-36 cytokines are overexpressed in affected skin of patients with inflammatory skin diseases, including atopic dermatitis and psoriasis (25)(26)(27)(28). The functional importance of this upregulation is supported by several recent findings: IL-36g mediates the alarmin function of the antimicrobial peptide LL37, and it functions as an alarmin that signals pathogen infections (20,29); injection of IL-36a promotes myeloid cell infiltration and their activation in the skin (30); tg mice overexpressing IL-36a in keratinocytes develop a psoriasis-like phenotype (31); the psoriasiform dermatitis that develops in mice after treatment with imiquimod depends on an IL-36-mediated cross-talk between dendritic cells and keratinocytes (32); and IL-36RA deficiency causes generalized pustular psoriasis in humans (33). Finally, a proinflammatory function of IL-36 cytokines in tissues other than the skin is emerging (34).…”

Elevated levels of soluble fractalkine and increased expression of CX3CR1 in neuropsychiatric systemic lupus erythematosus

“…Autoantibody and inflammatory cells are important pathogenic factors of NPSLE. Infiltration and activation of inflammatory cell often require the involvement of chemotactic factors (3). Fractalkine (FKN) is the only known member of the CX3C family at present which is a recently discovered chemotactic factor, the chemokine receptor of which is CX3CR1 (4).…”