Itch (or pruritus) refers to the unpleasant sensation that results in the innate behavior of scratching [1]. Most itch cases originate in the skin when pruritogens such as histamine stimulate the nerve endings of specialized neurons called pruriceptors. The cell bodies of the pruriceptors are located in the dorsal root ganglia (DRG) and trigeminal ganglia. The peripheral endings of these neurons form elaborate branches in the epidermis and dermis, and detect a wide range of chemical signals that cause itch [2], [3]. The central branches are located in the dorsal horn of the spinal cord, where they make synaptic connections with spinal neurons which relay the signal to the brain [4].

In this review, we will focus on the primary sensory neurons that mediate itch, the pruriceptors. DRG neurons can be categorized into roughly 16 sub-types [5]. Each sub-type encodes a distinct sensory modality (itch, pain, touch, temperature, proprioception, etc.). Importantly, each neuronal sub-type expresses a specific set of cell surface receptors that allows the detection of chemical signals in the skin. Single cell RNA sequencing (scRNAseq) revealed that there are 3 non-peptidergic (NP) types that mediate itch [1], [6] (Fig. 1). NP1 neurons are characterized by their expression of the G protein-coupled receptor (GPCR) MrgprD and respond to MrgprD agonist β-alanine to induce itch. NP2 neurons are marked by expression of another GPCR of the Mrgpr family, Mrgpra3, and mediate intense itch behavior in response to Mrgpra3 agonist chloroquine. NP3 neurons express serotonin receptors HTR7 and HTR2, interleukin-31 (IL-31) receptor, and the neuropeptide Nppb [1], [4], [7], [8], [9]. This review will summarize the current knowledge on microbial or immune factors that activate pruriceptors.

Itch is a symptom of many inflammatory skin diseases including psoriasis, atopic dermatitis (AD), acne, dermatophytosis and scabies [10]. Many skin diseases are associated with skin microbiome dysbiosis [11]. Healthy skin is colonized by diverse microbes including bacteria, fungi, and viruses that reside on the skin surface, hair follicles, sweat glands, and sebaceous glands [12]. Most microbes are beneficial or harmless to the host. More than 200 genera and 18 phyla of bacteria have been characterized on the skin, among them four phyla, Actinobacteria (36–51 %), Proteobacteria (11–16 %), Bacteroidetes (6–9 %) and Firmicutes (24–34 %) are dominant [13], [14]. The most common bacteria in moist sites of skin are Corynebacterium (Actinobacteria) and Staphylococcus (Firmicutes) [11], [15], [16], [17], [18]. Cutibacterium (Actinobacteria) species are most frequently found in oily areas, and dry sites of the skin show the most diverse microbiota. Most viruses in the skin microbiota are bacteriophages, but human papillomaviruses (HPV), especially cutaneous β and γ types, are frequently discovered on the skin's surface [19]. Malassezia is the dominant fungal genus in the skin while Epicoccum, Cryptococcus, Aspergillus, and Rhodotorula are also frequently seen [11]. In addition, small mites (Demodex spp.) reside in pilosebaceous follicles [19], [20]. Healthy microbiota contributes to skin barrier integrity, trains the immune system, and prevents pathogens from dominating the community and causing diseases [21].

Dysbiosis occurs when the microbiota becomes imbalanced, usually dominated by a pathogenic species at the expense of community diversity [22]. Many factors including aging, levels of hormones, pH, and immune dysregulation can impact microbial communities on the skin and cause dysbiosis [23]. 16S ribosomal RNA sequencing and metagenomic studies have been performed on many skin diseases and revealed many microbes associated with itchy skin diseases (Table 1). Skin lesions of AD patients are dominated by Staphylococci species, mostly S. aureus and S. epidermidis [24]. Acne is primarily caused by Cutibacterium acnes which resides in the hair follicles and sebaceous glands [25]. Fungal diseases such as athlete’s foot and jock itch are caused by dermatophytes, such as Microsporum canis and Trichophyton rubrum [26]. Scabies is attributed to the mite Sarcoptes scabiei [27]. Viral infections such as chickenpox (Varicella zoster virus) also present rashes and intense itch [28]. The molecules that activate the pruriceptors and the cell surface receptors that respond to these signals remain largely unknown for most diseases. This knowledge gap hinders the development of new drugs to alleviate itch, which is the top complaint of most patients suffering from skin diseases [10]. In this review, we combine current knowledge from the sensory biology, immunology, and microbiology fields, and discuss how microbes interact with the cutaneous neuroimmune system to cause itch. In Section 2, we review the microbial products that directly activate sensory neurons. In Section 3, we examine the indirect pathways by which microbes modulate the immune system and trigger itch via histamine and other immune cell-derived molecules.