Eccrine Sweat Contains IL-1α, IL-1β and IL-31 and Activates Epidermal Keratinocytes as a Danger Signal

Abstract

Eccrine sweat is secreted onto the skin's surface and is not harmful to normal skin, but can exacerbate eczematous lesions in atopic dermatitis. Although eccrine sweat contains a number of minerals, proteins, and proteolytic enzymes, how it causes skin inflammation is not clear. We hypothesized that it stimulates keratinocytes directly, as a danger signal. Eccrine sweat was collected from the arms of healthy volunteers after exercise, and levels of proinflammatory cytokines in the sweat were quantified by ELISA. We detected the presence of IL-1α, IL-1β, and high levels of IL-31 in sweat samples. To investigate whether sweat activates keratinocytes, normal human keratinocytes were stimulated with concentrated sweat. Western blot analysis demonstrated the activation of NF-κB, ERK, and JNK signaling in sweat-stimulated keratinocytes. Real-time PCR using total RNA and ELISA analysis of supernatants showed the upregulation of IL-8 and IL-1β by sweat. Furthermore, pretreatment with IL-1R antagonist blocked sweat-stimulated cytokine production and signal activation, indicating that bioactive IL-1 is a major factor in the activation of keratinocytes by sweat. Moreover, IL-31 seems to be another sweat stimulator that activates keratinocytes to produce inflammatory cytokine, CCL2. Sweat is secreted onto the skin's surface and does not come into contact with keratinocytes in normal skin. However, in skin with a defective cutaneous barrier, such as atopic dermatitis-affected skin, sweat cytokines can directly act on epidermal keratinocytes, resulting in their activation. In conclusion, eccrine sweat contains proinflammatory cytokines, IL-1 and IL-31, and activates epidermal keratinocytes as a danger signal.

Control of the Physical and Antimicrobial Skin Barrier by an IL-31–IL-1 Signaling Network

“…Although sweat is not harmful to healthy skin, it can aggravate the lesions of patients with AD. Sweat stimulates IL-1b and IL-1RA expression in keratinocytes, possibly due to the presence of IL-31, and also contains IL-1a and IL-1b (33)(34)(35)(36)94). The presence of these cytokines is consistent with their antimicrobial function as described in this study.…”

Quantitative Proteomics of the Human Skin Secretome Reveal a Reduction in Immune Defense Mediators in Ectodermal Dysplasia Patients

“…In addition, the comparison of the secretome of healthy individuals with that of ED patients suffering from reduced sweating enables us to indirectly evaluate the abundance of proteins on human skin derived from eccrine sweat glands. Several proteomic studies demonstrated that normal sweat obtained from healthy volunteers contains proteolytic enzymes, AMPs, as well as the proinflammatory cytokines IL-1 and IL-8 (Dai et al, 2013). We could not find IL-8 in the secretome of healthy individuals or ED patients, indicating that this interleukin is not very abundant on human skin.…”

Interleukin-1β-induced Reduction of CD44 Ser-325 Phosphorylation in Human Epidermal Keratinocytes Promotes CD44 Homomeric Complexes, Binding to Ezrin, and Extended, Monocyte-adhesive Hyaluronan Coats

“…It is also expressed in human epidermis (96) and HaCaT cells (97). This leads to activation of signaling pathways like ERK, p38, and NF-B and autocrine secretion of inflammatory cytokines like IL-8 and IL-1␤ (94,98). In addition to the IL-1R1, keratinocytes also express IL-1R2.…”