The skin is the largest organ of the human body. It controls body temperature and hydroelectrochemical balance, protects the organism, and maintains its integrated structures. Immunologically, the skin is endowed with a complex network of immune-functioning cells consisting of macrophages, Langerhans cells, and dendritic cells, as well as sensory neurons that detect damage.

The skin is frequently exposed to ultraviolet (UV) radiation, which, although critical for life, can also be a source of important alterations. The recent work by Hoeffel et al ¹ focuses on the injury caused by UVC radiation, being the most harmful type of radiation although it does not penetrate naturally the earth's atmosphere.² UV radiation contributes to a variety of skin alterations, including inflammation, degenerative aging, and cancer.² Inflammation is a response to harmful conditions and stimuli such as tissue damage. A successful acute inflammatory response results in the elimination of the tissue damage followed by a resolution and repair phase, which is mediated mainly by tissue resident and recruited macrophages.³ The number of macrophages increases during the inflammatory phase, peaks during the phase of granulation tissue, and declines during the maturation phase. Initially, proinflammatory macrophages infiltrate after injury to clean the wound of bacteria, debris, and dead cells. As the tissue begins to repair, the overall macrophage population transitions to one that promotes anti-inflammatory effects and the migration and proliferation of fibroblasts, keratinocytes, and endothelial cells to restore the dermis, epidermis, and vasculature, respectively.³

Since macrophages play an important role in tissue repair, it is important to elucidate the precise mechanisms by which these cells restore tissue homeostasis. In this sense, the detailed study by Hoeffel et al. elucidated the tissue repair cascade generated.¹ They described the pathway that begins from the nonpeptidergic GINIP⁺ sensory neurons releasing TAFA4 after skin exposure to UV. This promotes the production of IL-10 by embryonic-derived resident TIM4+ macrophages. The continuous release of IL-10 is essential for the maintenance of resident macrophage survival and for controlling inflammation. It also recruits fewer proinflammatory monocytes and more monocytes with an anti-inflammatory profile, leading to tissue repair and recovery of homeostasis (Figure 1).

TAFA4 is a secreted protein that attracts macrophages by chemotaxis through the formyl peptide receptor 1 (FPR1) in vitro, and it has been shown to be upregulated upon LPS-stimulation on macrophages.⁴ However, Hoefel et al have not found TAFA4 expression on CD206+ dermal macrophages or by bone marrow-derived macrophages following LPS stimulation. Furthermore, the authors have also not observed a chemotactic effect of TAFA4 on macrophages. They have proposed the existence of another receptor, different from FPR1, responsible for inducing its effect on dermal macrophages after skin injury.

IL-10 is a cytokine with potent anti-inflammatory properties that maintains the balance of the immune response. Hoefel et al. have shown in their work that macrophages and mast cells are the main IL-10 producers after irradiation; however, TAFA4 was only able to modulate IL-10 production in the macrophage population. This correlates with other tissues, such as the small intestine, where macrophages play an important role in maintaining gastrointestinal homeostasis through IL-10 production.⁵ Moreover, IL-10 deficiency in macrophages after drug-induced injury compromised the recovery of the small intestine epithelial barrier. In this regard, IL-10 has been proposed to be an attractive therapeutical target in inflammatory bowel diseases such as ulcerative colitis and Cronh's disease, but clinical results in humans have been disappointing without a clear beneficial effect. One possible explanation that has been proposed is that the cytokine is cleared before reaching its target due to its short half-life.⁶ Therefore, treatment with TAFA4 may result in the release of IL-10 in a more sustained manner and may be an alternative to IL-10 administration to treat other inflammatory skin diseases, such as pemphigus vulgaris and atopic dermatitis.

皮肤是人体最大的器官。它控制体温和水电化学平衡，保护有机体，并维持其整体结构。在免疫学上，皮肤具有由巨噬细胞、朗格汉斯细胞和树突状细胞以及检测损伤的感觉神经元组成的复杂免疫功能细胞网络。

皮肤经常暴露在紫外线 (UV) 辐射下，尽管紫外线对生命至关重要，但也可能是重要变化的来源。Hoeffel 等人最近的工作¹侧重于 UVC 辐射造成的伤害，这是最有害的辐射类型，尽管它不会自然穿透地球大气层。²紫外线辐射会导致多种皮肤变化，包括炎症、退化性衰老和癌症。²炎症是对有害条件和刺激（如组织损伤）的反应。成功的急性炎症反应导致组织损伤消除，随后进入消退和修复阶段，这主要由组织驻留和募集的巨噬细胞介导。³巨噬细胞数量在炎症期增加，在肉芽组织期达到高峰，在成熟期下降。最初，促炎巨噬细胞在受伤后浸润以清洁伤口上的细菌、碎片和死细胞。随着组织开始修复，整个巨噬细胞群转变为促进抗炎作用以及成纤维细胞、角质形成细胞和内皮细胞迁移和增殖的巨噬细胞群，从而分别恢复真皮、表皮和脉管系统。³

由于巨噬细胞在组织修复中发挥重要作用，因此阐明这些细胞恢复组织稳态的精确机制非常重要。从这个意义上说，Hoeffel 等人的详细研究。阐明了产生的组织修复级联。¹他们描述了从非肽能 GINIP ⁺感觉神经元在皮肤暴露于紫外线后释放 TAFA4 开始的途径。这促进了胚胎衍生的常驻 TIM4+ 巨噬细胞产生 IL-10。IL-10 的持续释放对于维持常驻巨噬细胞的存活和控制炎症至关重要。它还募集更少的促炎单核细胞和更多具有抗炎特性的单核细胞，从而导致组织修复和体内平衡的恢复（图 1）。

TAFA4 是一种分泌蛋白，可通过体外甲酰肽受体 1 (FPR1) 趋化性吸引巨噬细胞，并且已显示在 LPS 刺激巨噬细胞时上调。⁴然而，Hoefel 等人并未发现 TAFA4 在 CD206+ 真皮巨噬细胞或 LPS 刺激后由骨髓来源的巨噬细胞表达。此外，作者也没有观察到 TAFA4 对巨噬细胞的趋化作用。他们提出存在另一种不同于 FPR1 的受体，负责在皮肤损伤后诱导其对真皮巨噬细胞的影响。

IL-10 是一种具有强效抗炎特性的细胞因子，可维持免疫反应的平衡。霍费尔等人。在他们的工作中表明巨噬细胞和肥大细胞是辐照后主要的 IL-10 生产者；然而，TAFA4 只能调节巨噬细胞群中 IL-10 的产生。这与其他组织相关，例如小肠，其中巨噬细胞通过产生 IL-10 在维持胃肠道稳态中发挥重要作用。⁵此外，药物诱导损伤后巨噬细胞中 IL-10 的缺乏会损害小肠上皮屏障的恢复。在这方面，IL-10 已被提议作为炎症性肠病（如溃疡性结肠炎和克罗氏病）的有吸引力的治疗靶点，但在没有明显有益效果的情况下，人类的临床结果令人失望。一种可能的解释是，由于其半衰期短，细胞因子在达到其目标之前就被清除了。⁶因此，用 TAFA4 治疗可能会导致 IL-10 以更持续的方式释放，并且可以替代 IL-10 给药来治疗其他炎症性皮肤病，例如寻常天疱疮和特应性皮炎。